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Prolactin triggers pro-inflammatory immune responses in peripheral immune cells

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Prolactin triggers pro-inflammatory immune responses in peripheral immune cells

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Abstract

The peptide hormone prolactin (PRL) is produced by specialized cells in the anterior pituitary gland and in a number of sites outside the pituitary. Its biological actions consist of various roles in reproduction, lactation, and of a number of homeostatic biological activities that also include immune functions. Elevated serum PRL concentrations often correlate with abnormalities in immune responses. To determine the influence of PRL on human immune cells, human whole blood cultures were stimulated with lipopolysaccharide (LPS), supplemented with various concentrations of human recombinant PRL. We found that PRL, at concentrations achievable during pregnancy, anesthesia and medication, significantly amplified interleukin (IL)-12 and tumor necrosis factor-alpha (TNF-alpha) synthesis in LPS-stimulated cultures, in a dose-dependent manner. Conversely, synthesis of the anti-inflammatory cytokine IL-10 only increased significantly at very high concentrations of supplemented PRL. PRL alone was not able to induce any measurable secretion of TNF-alpha, IL-10, or IL-12 in non-stimulated, whole blood cultures. However, we demonstrated that PRL, by itself or in combination with LPS, causes an increase in the binding activity of the transcription factors nuclear factor-kappaB (NFkappaB) and interferon regulatory factor-1 (IRF-1), which are known to promote TNF-alpha and IL-12 secretion. These data suggest that PRL promotes pro-inflammatory immune responses via NFkappaB and IRF-1, which may affect pathophysiological processes in physiological hyperprolactinemic states.

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... Thus, it seems that chronic toxoplasmosis strongly participates in the generation of anti-Rib-P autoantibodies and development of neuropsychiatric manifestations in several ADs. PRL acts as an immunomodulator which may interfere with lymphocyte activation and cytokine production [419][420][421] . Activation of T lymphocytes mediated by the interaction of PRL, PRL-R, JAK2/ STAT5 pathways led to generation and release of several cytokines including IL-1, IL-4, IL-5, IL-6, IL-10, IFN-α, which stimulate activated B cells to proliferate and differentiate [422,423] . ...
... Brand et al [421] showed that PRL at physiological concentrations during pregnancy, anesthesia and medication, selectively and significantly enhanced IL-12 and TNF-α synthesis via NF-κB and interferon regulatory factor-1, at LPS-stimulated human immune cell cultures, in a dose-dependent manner. It was suggested that PRL at these elevated concentrations may strongly initiate an immune response, and then antigen-presenting cells may abnormally stimulate an immune response, finally leading to autoimmune reactivity [421] . ...
... Brand et al [421] showed that PRL at physiological concentrations during pregnancy, anesthesia and medication, selectively and significantly enhanced IL-12 and TNF-α synthesis via NF-κB and interferon regulatory factor-1, at LPS-stimulated human immune cell cultures, in a dose-dependent manner. It was suggested that PRL at these elevated concentrations may strongly initiate an immune response, and then antigen-presenting cells may abnormally stimulate an immune response, finally leading to autoimmune reactivity [421] . In humans, HPRL was associated with abnormalities in T-cell function and phenotype, abnormal T-cell proliferation [425,426] , inhibition of NK cells [427] , decreased neutrophil chemotaxis [428] , and increased activity of antigen-presenting cells [429] . ...
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T. gondii is globally distributed with a high proportion of the world population estimated to be seropositive, and in the U.S. the parasite is responsible for approximately million infections each year. T. gondii tachyzoites infect almost all nucleated cells and their intracellular multiplication and lifelong persistence in the host cells play an important role in triggering and development of autoimmune diseases (ADs). Latent chronic T. gondii infection may be associated with iron, iodine, and folic acid deficiencies that facilitate development and/or progression of ADs. The oral route is the natural portal of entry for the parasite and gastrointestinal manifestations are frequently reported in patients with ADs. Prolactin was found to bind to tachyzoites and this process impairs their adhesion and penetration into the host cells. Hyperprolactinemia (HPRL) demonstrated in patients with different ADs may therefore reflect host defense against T. gondii infection, and several antipsychotic drugs that induce HPRL also have antitoxoplasmatic activity. Leptin and obesity play an important role in triggering and maintenance of inflammation and autoimmunity. T. gondii infection causes a significant increase in leptin levels and there is a significant positive association between the parasite seropositivity and obesity. Nitric oxide (NO) acts as a proapoptotic as well as an antiapoptotic biomodulator, and have a variety effects on autophagy. Overproduction of NO during T. gondii infection causes dysfunction of both these processes and therefore hinders cleaning service of the apoptotic/autophagic cell-derived antigenic remnants, finally leading to triggering and development of ADs. Damage of the olfactory system associated with chronic latent T. gondii infection may affect olfactory bulb volume and various olfactory functions, being therefore at least in part responsible for the smell impairment in ADs. The potent proinflammatory response of macrophages to infection with T. gondii type II may explain the ability of the strain to cause pathology after oral infection. The parasite also triggers the secretion of antiinflammatory cytokines, such as IL-10, TGF-β, and generation of reactive nitrogen intermediates, thus suppressing the development of the TH1 immune responses and deactivating macrophages. Toxoplasma chronic infection-induced cytotoxic T lymphocyte exhaustion leads to development of ADs because of decreased polyfunctionality, cytotoxic capability, cytokine production, proliferative capacity, and metabolic deficiency. The process of CD4+ and CD8+ T-cell immune exhaustion inhibits the immune response, thus facilitating pathogen persistence. Systemic T. gondii infection triggers a rapid and persistent decrease in the size of naïve CD4+ T lymphocyte pooutput due to destruction of the thymic epithelium. Chronic parasite infections characterized by lower pathogen burden usually restricted to tissues, suggest alternative driving forces in the induction of T cell exhaustion, such as parasite encystations. A significantly lower occurrence of antibodies to persistent viral infections reported in patients with some ADs compared with controls may be due to ol, and a long-term thymic atrophy and suppressed (exhausted) function of host B cells. Both T. gondiiand viral-associated inflammatory processes may be mutually overlapping which lead to worsening or improving clinical course of ADs depending on final temporary or stable proinflammatory/ antiinflammatory cytokine constellations. Dual-affinity T cell receptors may partly be responsible for frequently observed coinfections of T.gondii with some viruses and bacteria. Commonly reported comorbidities in ADs may at least in part be explained by liver damage caused by the pathogen. Vitamin D deficiency is often found in patients with ADs and there is vast evidence that the vitamin has an important beneficial impact on both innate and acquired immunity. Moreover, vitamin D exerts toxoplasmacidal effects and therefore should find a firm place in treatment regimens used in ADs.
... It also aims to include an integrative discussion of previous studies from our group focused on these hormones. Studies on inflammatory markers will also be discussed due to the close relationship between inflammation and some hormones, particularly HPA axis hormones and prolactin (Brand et al., 2004;Soria et al., 2017). The role of these hormones in psychotic disorders will be reviewed in two parts: 1) vulnerability to psychosis and 2) negative and cognitive symptoms. ...
... Prolactin promotes pro-inflammatory immune responses via nuclear factor-kappa B and interferon regulatory factor-1 (Brand et al., 2004) and regulates monocyte/macrophage function in vitro (Carvalho-Freitas et al., 2008). The inflammatory hypothesis of schizophrenia suggests that inflammatory processes might be involved in the pathogenesis of this mental illness (Howes and McCutcheon, 2017;Soria et al., 2017) based on the observed pro-inflammatory state in FEP and chronic patients with schizophrenia compared with that in HS and increased inflammation found in patients with relapses that improves after antipsychotic treatment (Miller et al., 2011). ...
... The largest study to date, the NAPLS project, suggest that several inflammatory markers including IL-1β, IL-7, IL-8, matrix metalloproteinase 8 (MMP-8) might be associated to the risk of psychosis transition (Perkins et al., 2015). Although in this study prolactin was not included in the final panel of 15 out of 117 baseline analytes that significantly predicted psychosis transition, given the pro-inflammatory activity of prolactin (Brand et al., 2004), more studies are needed to explore the potential prolactininflammation link in relation to the vulnerability to develop a psychotic disorder. ...
Article
For many years, the study of the psychotic phenotpe and approach to treatment of schizophrenia has been focused on positive psychotic symptoms, although the functional outcome is more clearly associated with negative and cognitive symptoms. Recently, there has been a growing interest in identifying biomarkers associated with these symptoms at early stages of the illness, including the risk of psychosis in vulnerable individuals (at-risk mental states [ARMS]). In this paper, the role of cortisol and prolactin in the clinical expression of psychosis will be reviewed. In examination of the role of these hormones and the risk of developing a psychotic disorder in ARMS individuals, previous studies have suggested potential roles for both cortisol and prolactin. The study of cognitive abilities in recent-onset psychotic patients has suggested that affected cognitive domains differ depending upon the studied hormones: cortisol (processing speed, verbal and working memory) and prolactin (processing speed), with several studies suggesting that there are sex-differences in these associations. All of these results suggest that both cortisol and prolactin contribute to the pathogenesis and clinical expression of psychotic disorders.
... However, this effect was reverted when the membranes were co-incubated with a JAK2/STAT5 pathway inhibitor, indicating that this inhibition is PRL dependent (Thomas et al., 2015). These results are in agreement with previous evidence indicating that PRL can inhibit the basal production of TNF-α in term human fetal membranes (Zaga-Clavellina et al., 2014a,b); however, other studies involving LPS-stimulated whole blood cultures showed that co-stimulation with high levels of PRL (300 ng/mL) upregulated TNF-α, supporting the concept of the tissue-specific action of PRL (Brand et al., 2004) IL-1β is also an inflammatory modulator that plays a central role during labor at term (Chao et al., 1994). Indeed, maternal and fetal tissues, such as fetal membranes, produce high levels of this cytokine during the onset and progression of labor under both physiological and pathological conditions (Chao et al., 1994;Gomez-Lopez et al., 2017), including infection (Menon et al., 2009). ...
... Although the capacity of PRL to increase IL-10 has been extensively studied in professional immune cells (Brand et al., 2004;Matalka, 2003), in the present study we did not find a significant effect of PRL on IL-10. However, this could suggest alternative tissue-specific anti-inflammatory mechanisms. ...
... The ubiquitous PRL receptor belongs to the class I cytokine receptor superfamily, which also includes the receptors of several interleukins and hematopoietic growth factors (Bazan, 1989(Bazan, , 1990. The hormone promotes the activity of macrophages (Edwards et al., 1987), inhibits the apoptosis of T-lymphocytes caused by glucocorticoids (Krishnan et al., 2003), and stimulates the production of tumor necrosis factor-α and IL-12 (Brand et al., 2004). Considering the immunomodulatory actions of PRL, several studies have focused on its potential involvement in bovine mastitis. ...
... Because CNS-infected cows appear to produce more milk than noninfected cows (Compton et al., 2007;Schukken et al., 2009;Piepers et al., 2010), we investigated the milk yield and the response of milk PRL after CNS challenge in clinically healthy dairy heifers. A plethora of evidence implicates PRL as an immunomodulating factor (Edwards et al., 1987;Krishnan et al., 2003;Brand et al., 2004;Boutet et al., 2007). ...
Article
Coagulase-negative staphylococci (CNS) are the most common bacteria involved in subclinical mastitis in dairy cows. Remarkably, CNS-infected dairy heifers produce more milk than uninfected heifers. Because the lactation hormone prolactin (PRL) is also involved in mammary gland immunity, we investigated the milk PRL response and the mammary quarter milk yield following experimental CNS challenge. Eight healthy Holstein-Friesian heifers in mid-lactation were experimentally infected using a split-udder design with 3 different CNS strains: one Staphylococcus fleurettii (from sawdust bedding) and 2 Staphylococcus chromogenes strains (one isolate from a teat apex, the other isolate from a chronic intramammary infection). Three mammary quarters per heifer were simultaneously inoculated with 1.0 × 106 cfu, whereas the remaining mammary quarter was infused with sterile phosphate-buffered saline, serving as a control. An existing radioimmunoassay was modified, validated, and used to measure PRL frozen-thawed milk at various time points until 78 h after challenge. The mean milk PRL level tended to be higher in the CNS-challenged mammary quarters compared with the control mammary quarters (7.56 and 6.85 ng/mL, respectively). The increase in PRL over time was significantly greater in the CNS-challenged mammary quarters than in the control mammary quarters. However, no difference was found in the PRL response when comparing each individual CNS strain with the control mammary quarters. The mean mammary quarter milk yield tended to be lower in the CNS-infected mammary quarters than in the control mammary quarters (1.73 and 1.98 kg per milking, respectively). The greatest milk loss occurred in the mammary quarters challenged with the intramammary strain of S. chromogenes. Future observational studies are needed to elucidate the relation between PRL, the milk yield, and the inflammatory condition, or infection status, of the mammary gland.
... In the last century, clinicians observed that NPM was often accompanied by hyperprolactinemia, with PRL levels exceeding the laboratory reference range (high: 400-500 mIU/L) on 2 independent occasions [27]. To date, a few reports have documented peripheral hormone fluctuations during NPM in mammals [28,29]. We counted the number of mastitis patients who were hospitalized from June 2009 to August 2018 in the Department of Breast Surgery at our hospital. ...
... The roles of PRL in stimulating the proliferation and inflammatory activity of immune cells have also been investigated in humans. Brand et al. [28] demonstrated that PRL, alone or in combination with lipopolysaccharide, promotes the secretion of TNF-α and IL-12 via NF-κB and interferon regulatory factor-1 in the peripheral white blood cells (WBCs) of patients with hyperprolactinemia, which in turn triggers immune responses and plasma cell infiltration in the breast. Friedrich et al. [32] found that serum PRL concentrations were associated with several inflammatory biomarkers, such as the IL-6 level and WBC count, by analyzing 1,839 men and 1,905 women. ...
Article
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Background: Plasma cell mastitis (PCM), also known as mammary duct ectasia, is a chronic nonbacterial breast inflammation characterized by duct expansion and plasma cell infiltration. The severe and intense clinical manifestations profoundly affect the quality of life of female patients. Although the pathological process of PCM is known to include four stages (duct dilatation, inflammation, abscess and fistula), there is still lack of imaging techniques and serum markers with high specificity in clinical practice. Due to recurrent acute attacks and the prolonged healing process of the disease, most patients choose to accept mastectomy. Summary: We searched for studies, reports and reviews referring to PCM in the past 20 years; more than half of the results were related to animal studies, and little attention has been paid to human beings, which may explain the frequent misdiagnosis of PCM as breast cancer and the limited treatment options. This review focuses on the current diagnostic methods and markers for PCM and hierarchically discusses the typical clinical features, etiological causes and relevant molecular mechanisms of PCM. Key messages: We herein highlight the urgent need to develop more specific and sensitive biomarkers in the clinical laboratory. It will help to establish a standardized flowchart for the diagnosis and treatment of PCM in order to improve recovery for female patients.
... All 26 mNSCLC patients were administered an average of 14 doses of NIVO (range, [8][9][10][11][12][13][14][15][16][17][18]. At the time of the analysis, the median follow-up was around 8 months. ...
... PRL has a double effect on the immune system: it plays an important role in maturation and differentiation of T cells [15] . Moreover, it seems to have a dose-dependent mechanism of action, since high PRL concentrations may activate a negative feedback system through IL-10, thus limit- ing the pro-inflammatory reactivity [16] . Twenty out of 26 patients enrolled in the study developed hyperprolactinemia during treatment with NIVO, while 6 patients had stable PRL levels during the treatment. ...
Article
Abstract BACKGROUND/AIMS: Prolactin (PRL) is a peptide hormone and several studies have demonstrated its role as a cytokine in human T cell-mediated immunity. We are unaware if PRL is a positive or negative immunomodulator, but its effects on the regulation of T cells could inhibit the antitumor activity elicited by nivolumab (NIVO). We aimed to assess whether the occurrence of hyperprolactinemia in metastatic non-small cell lung cancer (mNSCLC) patients treated with NIVO is associated with poor clinical outcomes. METHODS: We evaluated 26 mNSCLC patients treated with NIVO. Blood samples were collected in every patient to evaluate PRL basal levels before starting the therapy with NIVO and before each following administration of NIVO. All patients underwent a conventional CT to investigate the effect of therapy according to Immune-related Response Evaluation Criteria in Solid Tumors (IrRECIST). RESULTS: Twenty patients (77%) developed hyperprolactinemia during the treatment, whereas 6 patients (23%) had stable levels of PRL during the therapy (p = 0.001). A total of 95% of the 20 patients with hyperprolactinemia had progressive disease (PD), according to CT results, whereas only 2 patients (33%) out of 6 with stable PRL levels had PD (p = 0.004). CONCLUSIONS: Hyperprolactinemia in mNSCLC patients treated with NIVO could potentially represent a negative early predictive factor for poor clinical outcomes, thus anticipating PD shown by CT scan.
... The Jörg-Matthias Brand team finds that prolactin stimulates a pro-inflammatory immune response on peripheral inflammatory cells [42]. Prolactin, at concentrations achievable during medication, pregnancy, and anesthesia, significantly enhances the synthesis of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12 in lipopolysaccharideactivated human whole blood cultures. ...
... Prolactin, at concentrations achievable during medication, pregnancy, and anesthesia, significantly enhances the synthesis of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12 in lipopolysaccharideactivated human whole blood cultures. These data suggest that prolactin may affect pathophysiological processes in physiological hyperprolactinemic disorders [42]. ...
Article
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Prolactin-releasing Peptide (PrRP) is a neuropeptide whose receptor is GPR10. Recently, the regulatory role of PrRP in the neuroendocrine field has attracted increasing attention. However, the influence of PrRP on macrophages, the critical housekeeper in the neuroendocrine field, has not yet been fully elucidated. Here, we investigated the effect of PrRP on the transcriptome of mouse bone marrow-derived macrophages (BMDMs) with RNA sequencing, bioinformatics, and molecular simulation. BMDMs were exposed to PrRP (18 h) and were subjected to RNA sequencing. Differentially expressed genes (DEGs) were acquired, followed by GO, KEGG, and PPI analysis. Eight qPCR-validated DEGs were chosen as hub genes. Next, the three-dimensional structures of the proteins encoded by these hub genes were modeled by Rosetta and Modeller, followed by molecular dynamics simulation by the Gromacs program. Finally, the binding modes between PrRP and hub proteins were investigated with the Rosetta program. PrRP showed no noticeable effect on the morphology of macrophages. A total of 410 DEGs were acquired, and PrRP regulated multiple BMDM-mediated functional pathways. Besides, the possible docking modes between PrRP and hub proteins were investigated. Moreover, GPR10 was expressed on the cell membrane of BMDMs, which increased after PrRP exposure. Collectively, PrRP significantly changed the transcriptome profile of BMDMs, implying that PrRP may be involved in various physiological activities mastered by macrophages.
... In addition to its lactational role, PRL has been shown to have a significant involvement in immune functions, playing an important role in signalling between immune and neuro-endocrine systems (for review, see Yu- Lee, 2002). Prolactin has been found to trigger a pro-inflammatory immune response and stimulate PMN chemotaxis (Brand et al., 2004;Boutet et al., 2007). Upon PRL stimulation, bovine mammary epithelial cells significantly amplified mRNA expression for several proinflammatory cytokines, such as: IL-1, IL-6, IL-8, granulocyte macrophage colony stimulating factor (GMCSF; delays PMN apoptosis) and TNF-Į (Boutet et al., 2007). ...
... Prolactin has been shown to influence and regulate the humoral and cellular immune response (for review see Yu- Lee, 2002). Several studies suggest that PRL triggers the pro-inflammatory immune response and stimulates chemotaxis, and that PRL within physiologically achievable concentrations may be selectively involved in PMN migration (Brand et al., 2004;Boutet et al., 2007). The PRL levels in milk (PRLm) and blood (PRLb) were subjects of interest in paper III and IV. ...
... Immunomodulation of prolactin appears to be an increase in transcription factors such as IRF and NF-κB which play a role in immune function. 22 Brand et al (2004), have shown that prolactin increases the release of TNF-α and IL-2 from mononuclear cells by stimulation of LPS (lipopolysaccharide). TNF-α and IL-2 are important cytokines as mediators of inflammation, complications of sepsis and autoimmunity. 23 There were several limitations of this study. ...
... 22 Brand et al (2004), have shown that prolactin increases the release of TNF-α and IL-2 from mononuclear cells by stimulation of LPS (lipopolysaccharide). TNF-α and IL-2 are important cytokines as mediators of inflammation, complications of sepsis and autoimmunity. 23 There were several limitations of this study. This study did not exclude the presence of psychological stress that can increase prolactin levels. ...
Article
Background: Systemic inflammatory response syndrome (SIRS) is a state of systemic inflammatory activation by various causes. SIRS have a high mortality rate. Prolactin is known to regulate cellular function of immune system. Neutrophil-lymphocyte ratio (NLR) is simple, cost effective and easy parameter that currently used as inflammation marker.Objective: The aims of this study is to determine the correlation between prolactin serum with NLR in SIRS patients.Methods: A cross sectional study was conducted on 50 clinically SIRS patients. Prolactin serum was measured by enzyme linked immunosorbent assay (ELISA) and NLR was calculated manually from absolute neutrophil and lymphocyte count measured by automatic hematology analyzer. Non-parametric Spearman test was used to analyze the correlation between prolactin with NLR.Results: Median value of serum prolactin level was 11.32 ng/mL (2.76-194.81), whereas the mean value NLR was 16.36 ± 11.58. The correlation between prolactin levels with NLR was r = 0.345, p = 0.014.Conclusion: There is a weak positive significant correlation between prolactin with neutrophil lymphocyte ratio in SIRS
... The effect of PRL on lipolysis in humans is unclear, as evidence is inconsistent (e.g., Brandebourg et al., 2007;Grattan, 2015). Though its effects may be modulated by conditions (such as stress), PRL is generally thought to lead to proliferation of lymphocytes and, thereby, increase investment in immune function (e.g., Brand et al., 2004). ...
Article
Which hormones are implicated in human social bonding and affiliation? And how does field research speak to this issue? We begin by laying out a broad view of how endocrine hormones in general modulate life history allocations of energy and other resources, and the ways in which their neuromodulatory functions must be understood within a broader conceptualization of how they have been shaped to affect allocations. We then turn to four specific hormones or hormone families that have received much attention: oxytocin, opiods, prolactin, and progesterone. Each plays a role in regulating psychological capacities and propensities that underlie individuals' interactions with important social targets. Yet in no case is it clear exactly what regulatory roles these hormones play. We suggest several directions for future research.
... Prolactin strongly persuades the innate and adaptive immune responses, managing the maturation of CD4− CD8− thymocytes to CD4+ CD8+ T cells, through IL-2 receptor expression (16,17). A direct correlation between PRL levels and the number of B and CD4+ T lymphocytes has been reported (18). Indeed, hyperprolactinemia can impair B-cell clonal deletion, deregulate receptor editing and diminish the threshold for activation of B cells, promoting auto-reactivity (19)(20)(21). ...
Article
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The great asymmetry of autoimmune diseases between genders represents one of the most enigmatic observations among the mosaic of autoimmunity. Sex hormones are believed to play a crucial role on this dimorphism. The higher prevalence of autoimmunity among women at childbearing ages, disease onset/relapses during pregnancy, and post-partum are some of the arguments that support this hypothesis. Certainly, motherhood represents one of the most remarkable challenges for the immune system, which not only has to allow for the conceptus, but also has to deal with complex endocrine alterations. Hormonal homeostasis is known to exert a crucial influence in achieving a competent and healthy immune system. Prolactin (PRL) has a bioactive function acting as a hormone and a cytokine. It interferes with immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Likewise, hyperprolactinemia has been described in relation to the pathogenesis and activity of several autoimmune disorders. Dopamine is an effective inhibitor of PRL secretion due to either a direct influence on the hypophysis or stimulation of postsynaptic dopamine receptors in the hypothalamus, arousing the release of the PRL inhibitory factor. Hence, dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, we attempt to provide a critical overview of the link between PRL, autoimmune diseases, and motherhood.
... PRL, by itself or in combination with LPS, causes an increase in the binding activity of the transcription factors nuclear factor-kappa B (NF kappa B) and interferon regulatory factor-1 (IRF-1), which are known to promote TNF-α and IL-12 secretion. These data suggest that PRL promotes pro-inflammatory immune responses via NF kappa B and IRF-1, which may affect pathophysiological processes in HPRL [21]. ...
Article
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Prolactin, a 23-kDa peptide hormone, is produced by the anterior pituitary gland and extrapituitary sites including the immune cells. Prolactin (PRL) participates in innate and adaptive immune response. PRL stimulates the immune cells by binding to receptor (PRL-R). Binding of PRL to its receptor activates the Janus kinase-signal transducer (JAK-STAT). Activation of these cascades results in endpoints such as immunoestimulator and immunosupressor action. Prolactin belongs to the network of immune-neuroendocrine interaction. Hyperprolactinemia has been found in patients with systemic lupus erythematosus (SLE), and new evidence has confirmed a significant correlation between serum PRL levels and disease activity. PRL participates in activation of SLE during pregnancy and in pathogenesis of lupus nephritis, neuropsychiatric, serosal, hematologic, articular, and cutaneous involvement. Hyperprolactinemia was associated with increase IgG concentrations, anti-DNA antibodies, immune complex, glomerulonephritis, and accelerated mortality in murine lupus. Bromocriptine, a dopamine analog that suppresses PRL secretion, was associated with decreased lupus activity, prolonged lifespan, and restoration of immune competence in experimental model. In clinical trials, bromocriptine and derivative drugs showed beneficial therapeutic effect in treating human lupus, including pregnancy. Taken together, clinical and experimental results leave little doubt that PRL indeed contributes to the pathogenesis and clinical expression of SLE.
... 8 In addition, high prolactin levels may increase proinflammatory response indicating an involvement in human immune dysfunction. 15,16 Previous study found potential relationship between elevated free testosterone level and an insulin resistance status in hyperprolactinemia women. 17 Moreover, previous study found that HOMA-IR had significant correlation with free testosterone in premenopausal T2DM women with high insulin level only, but no significant correlation with total testosterone and SHBG was found among all study patients with the high, low, or near normal fasting insulin level. ...
Article
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ABSTRACT Beta cell dysfunction and insulin resistance are believed to cause persistent hyperglycemia which characterizes type 2 diabetes. Previous study found potential relationship between elevated free testosterone level and an insulin resistance status in hyperprolactinemia women. Treatment with different doses of metformin result in a significant reduction in prolactin level. This study is designed to explore the potential role of metformin in improving β cell function via its effect on ameliorating metabolic and hormonal parameters in type 2 diabetic women by direct or indirect relationship. A 20 middle age newly diagnosed type II diabetes mellitus female patients treated with 1500mg metformin daily for 6 months. Fasting blood glucose, fasting serum insulin, HOMA-IR, HOMA-B, serum prolactin, total and free testosterone were measured. Following three to six months with metformin therapy, significant improvement in glycemic parameters, insulin resistance, β cell function was clear(P<0.05). Similarly for endogenoustotal and free testosterone, and serum prolactin levels were significantly reduced (P<0.05). Fasting serum insulin positively correlated only with serum prolactin after 6 months of metformin therapy (P<0.05). Fasting serum insulin and IR showed negative correlation with free testosterone at the baseline and after metformin therapy (P<0.05). The reduction in serum prolactin and endogenous total and free testosterone following metformin therapy may potentially reduce fasting serum insulin, insulin resistance, and thereby improves β cell function. Keywords: Type II diabetes mellitus, prolactin, testosterone, metformin, HOMA-IR, HOMA-B.
... 8 In addition, high prolactin levels may increase proinflammatory response indicating an involvement in human immune dysfunction. 15,16 Previous study found potential relationship between elevated free testosterone level and an insulin resistance status in hyperprolactinemia women. 17 Moreover, previous study found that HOMA-IR had significant correlation with free testosterone in premenopausal T2DM women with high insulin level only, but no significant correlation with total testosterone and SHBG was found among all study patients with the high, low, or near normal fasting insulin level. ...
Article
Abstract Background Beta cell dysfunction and insulin resistance are believed to cause persistent hyperglycemia which characterizes type 2 diabetes. Previous study found potential relationship between elevated free testosterone level and an insulin resistance status in hyperprolactinemia women.Treatment with different doses of metformin result in a significant reduction in prolactin level. Objective This study is designed to explore the potential role of metformin in improving β cell function via its effect on ameliorating metabolic and hormonal parameters in type 2 diabetic women by direct or indirect relationship. Methods A 20 middle age newly diagnosed type II diabetes mellitus female patients treated with 1500mg metformin daily for 6 months. Fasting blood glucose,fasting serum insulin, HOMA-IR, HOMA-B,serum prolactin, total and free testosterone were measured. Results Following three to six months with metformin therapy, significant improvement in glycemic parameters,insulin resistance, β cell function was clear(P<0.05). Similarly for endogenoustotal and free testosterone, and serum prolactin levels were significantly reduced (P<0.05). Fasting serum insulin positively correlated only with serum prolactin after 6 months of metformin therapy (P<0.05). Fasting serum insulinand IR showed negative correlation with free testosterone at the baseline and after metformin therapy (P<0.05). ConclusionThe reduction in serum prolactin and endogenous total and free testosterone following metformin therapy may potentially reduce fasting serum insulin, insulin resistance, and thereby improves β cell function.
... The one exception (not in the list of prolactin-regulated genes compiled by Ingenuity Pathway Analysis) was for the cytokine gene IL10, which was more expressed in SL +/− than in SL −/− heifers. Prolactin stimulates IL10 secretion in immune and mammary epithelial cells (Kim et al., 2003;Matalka, 2003;Brand et al., 2004). ...
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The SLICK1 mutation in the prolactin receptor (PRLR) results in a short-hair coat and increased ability to regulate body temperature during heat stress. It is unclear whether the mutation affects capacity for sweating. The objective of this observational study was to evaluate whether the SLICK1 mutation in PRLR alters characteristics of skin related to sweat gland abundance or function. Skin biopsies from 31 Holstein heifers, including 14 wild-type (SL−/−) and 17 heterozygous slick (SL+/−), were subjected to histological analysis to determine the percent of the surface area of skin sections that are occupied by sweat glands. We detected no effect of genotype on this variable. Immunohistochemical analysis of the forkhead transcription factor A1 (FOXA1), a protein essential for sweating in mice, from 6 SL−/− and 6 SL+/− heifers indicated twice as much FOXA1 in sweat glandular epithelia of SL+/− heifers as in SL−/− heifers. Results from RNA sequencing of skin biopsies from 5 SL−/− and 7 SL+/− heifers revealed few genes that were differentially expressed and none that have been associated with sweat gland development or function. In conclusion, results do not support the idea that the SLICK1 mutation changes the abundance of sweat glands in skin, but do show that functional properties of sweat glands, as indicated by increased abundance of immunoreactive FOXA1, are modified by inheritance of the mutation in PRLR.
... Also, the number and function of circulating NK cells and mature T cells were reduced in patients with hyperprolactinemia (32-394 ng/ml) [149][150][151], and in vitro studies showed that higher (100-200 ng/ ml) and lower (12-25 ng/ml) PRL levels inhibit and stimulate, respectively, the proliferation of blood NK cells and T cells [47]. Likewise, lower concentrations of PRL (\20 ng/ml) were more effective than higher PRL levels (100 ng/ml) in stimulating antibody production by circulating lymphocytes from patients with systemic lupus erythematosus [152]; while high doses of PRL enhanced the in vitro release of proinflammatory mediators by peritoneal macrophages and peripheral blood mononuclear cells, a much higher dose induced the release of anti-inflammatory IL-10 [153,154]. ...
Article
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Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease destroying articular cartilage and bone. The female preponderance and the influence of reproductive states in RA have long linked this disease to sexually dimorphic, reproductive hormones such as prolactin (PRL). PRL has immune-enhancing properties and increases in the circulation of some patients with RA. However, PRL also suppresses the immune system, stimulates the formation and survival of joint tissues, acquires antiangiogenic properties upon its cleavage to vasoinhibins, and protects against joint destruction and inflammation in the adjuvant-induced model of RA. This review addresses risk factors for RA linked to PRL, the effects of PRL and vasoinhibins on joint tissues, blood vessels, and immune cells, and the clinical and experimental data associating PRL with RA. This information provides important insights into the pathophysiology of RA and highlights protective actions of the PRL/vasoinhibin axis that could lead to therapeutic benefits.
... Serum CA125 rises in 10%-20% of patients with early stages of EC and only in 25% of asymptomatic patients with recurrence. Measurement of CA125 is highly performed in the diagnosis of advanced stages EC (6)(7)(8)(9). Although human epididymis protein 4 (HE4) exists in normal tissues such as epithelium of mammary glands, female genital tract, vas deferens, respiratory glands, colonic mucosa, and salivary glands, its serum titers increase in cancer tissues, such as mesothelioma and lung, endometrial, breast, digestive tract, and interstitial tissue cancers; however, the highest serum HE4 levels are seen in ovarian cancer in women and lung cancer in men (10). ...
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Objectives: Endometrial cancer (EC) is the most common malignancy of the female reproductive system. To date, no good marker for screening or disease monitoring of EC is available. The objective of this study was to investigate the sensitivity and specificity of CA125 and human epididymis protein 4 (HE4) in detection of EC. Materials and Methods: This case-control study was carried out on 40 women with EC and 60 women without cancer. Serum samples were prospectively obtained from all patients. Cut-off points for HE4 and CA125 were considered 70 pmol/L and 35 U/mL, respectively. The level of statistical significance is set at P < 0.05. Results: The ROC-AUC, for HE4 was 0.82 and CA125 was 0.73 and for combination of HE4 and CA125 was 0.89. Compared to CA125, HE4 had higher sensitivity (57.7% vs. 40%), equal specificity (93.3% vs. 95%), equal positive predictive value (PPV) (85% vs. 84.2%) and higher negative predictive value (NPV) (76.71% vs. 70.37%) and in combination of two tumor markers sensitivity, specificity, PPV and NPV were 62.5%, 93.3%, 86.2% and 78.9%, respectively. It was clear that combination of two markers had higher sensitivity and higher NPV to detect EC, than each marker alone. HE4 and CA125 were significantly elevated in EC compared to controls (P < 0.001). There was significant correlation between median HE4 and age of the patients (r = 0.48, P = 0.002) and stage of the disease (r =0.50, P = 0.001). There was no significant correlation between CA125 and age, stage or grade of the disease (P = 0.39, P = 0.08 and P = 0.9, respectively). Conclusion: Our study showed that serum HE4 levels alone and in combination with CA125 are sensitive markers in diagnosing EC.
... Prolactin promotes pro-inflammatory immune responses via NFκB and interferon regulatory factor (IRF-1). These cited factors are known to induce TNF-α increase, considered essential inflammation mediator [35], which can affect pathophysiological processes during hyperprolactinemic conditions [8]. TNF-α contributes to a dysregulated inflammatory response in the airways of asthmatics, in part by inducing the epithelial expression of pro-inflammatory cytokines and adhesion molecules [24], which was observed in the hyperprolactinemic group with increases in IL-6, IL-10 and IFN-g secreting cells. ...
Article
Aims: Prolactin is a major immunomodulator. The present study evaluated the effects of short-term hyperprolactinemia induced by domperidone before ovalbumin antigenic challenge on the lung's allergic inflammatory response. Main methods: To induce hyperprolactinemia, domperidone was injected in rats at a dose of 5.1 mg·kg−1 per day, i.p., for 5 days from 10th to 14th day after OVA immunization. Total and differential leukocyte counts from bronchoalveolar lavage (BAL), femoral marrow lavage (FML), and blood were analyzed. The percentages of mucus and collagen production were evaluated. Levels of corticosterone and prolactin in serum, interleukin-4 (IL-4), IL-6, IL- 10, tumor necrosis factor α (TNF-α) in lung explants supernatants were measured and interferon gamma (IFN- γ) in bronchiolar lavage cells suspensions (BAL) was measured. Key findings: The rats that were subjected to short-term hyperprolactinemia exhibited a decrease in leukocyte counts in bronchoalveolar lavage, cellularity decrease in femoral marrow lavage fluid, a lower percentage of mucus, and an increase in lung IL-4, IL-6, IL-10, TNF-α and IFN-γ expression. Significance: Hyperprolactinemia induced before antigenic challenge decreased allergic lung inflammation. These data suggest that prolactin may play a role in the pathophysiology of asthma. The present study demonstrates a prospective beneficial side effect of domperidone for asthmatic patients
... Unlike the above neuroendocrine mediators with antiinflammatory actions, the anterior pituitary hormone PRL is generally thought to promote inflammatory responses by stimulating the expression of pro-inflammatory cytokines (Brand et al., 2004). Although PRL levels were found to be increased in patients with systemic inflammatory response syndrome (SIRS) and during the early stage of sepsis (Maxime et al., 2007), PRL responses to experimental endotoxin administration in humans have not been investigated so far. ...
Article
Impaired mood and increased anxiety represent core symptoms of sickness behavior that are thought to be mediated by pro-inflammatory cytokines. Moreover, excessive inflammation seems to be implicated the development of mood/affective disorders. Although women are known to mount stronger pro-inflammatory responses during infections and are at higher risk to develop depressive and anxiety disorders compared to men, experimental studies on sex differences in sickness symptoms are scarce. Thus, the present study aimed at comparing physiological and psychological responses to endotoxin administration between men and women. Twenty-eight healthy volunteers (14 men, 14 women) were intravenously injected with a low dose (0.4 ng/kg) of lipopolysaccharide (LPS) and plasma concentrations of cytokines and neuroendocrine factors as well as negative state emotions were measured before and until six hours after LPS administration. Women exhibited a more profound pro-inflammatory response with significantly higher increases in tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, the LPS-induced increase in anti-inflammatory IL-10 was significantly higher in men. The cytokine alterations were accompanied by changes in neuroendocrine factors known to be involved in inflammation regulation. Endotoxin injection induced a significant increase in noradrenaline, without evidence for sex differences. The LPS-induced increase in cortisol was significantly higher in woman, whereas changes in dehydroepiandrosterone were largely comparable. LPS administration also increased secretion of prolactin, but only in women. Despite these profound sex differences in inflammatory and neuroendocrine responses, men and women did not differ in endotoxin-induced alterations in mood and state anxiety or non-specific sickness symptoms. This suggests that compensatory mechanisms exist that counteract the more pronounced inflammatory response in women, preventing an exaggerated sickness response. Disturbance of these compensatory mechanisms by environmental factors such as stress may promote the development of affective disorders in women. Copyright © 2015. Published by Elsevier Inc.
... [7] In addition, high prolactin levels may increase proinflammatory response indicating an involvement in human immune dysfunction. [13,14] A recent shift towards novel markers of cardiovascular risk has emerged, particularly towards C reactive protein (CRP) which has been found to be a good predictor of vascular events. In addition to being an inflammation marker, there are several data that suggest a direct role of CRP in atherogenesis via complement activation, expression of adhesion molecule, and mediation of the uptake of low density lipoprotein (LDL) by macrophages. ...
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ABSTRACT Introduction: The role of hypothalamus and neurohormonal circuitry in glycemic control that incorporates the cross talk between blood born factors and neurons is considered an important mechanism involved in diabetes pathophysiology. The theory emphasizes that the circadian neuroendocrine rhythm (Dopamine, 5-HT and norepinephrine) in the hypothalamus is altered in diabetes mellitus. Many experimental studies indicate an influence of prolactin on type 2 diabetes mellitus. This study aims to investigate the effect of different doses of metformin on prolactin and C-reactive protein in newly diagnosed female with diabetes mellitus. Material and methods: 60 newly diagnosed type 2 diabetic patients were divided into three groups according to the dose of metformin in addition to 20 diabetic free (control group). All patients were treated with metformin for 6 months. Result: Treatment with different doses of metformin result in a significant reduction in prolactin and C-reactive protein levels. Our data indicate that metformin significantly decreases prolactin level possibility via increasing the dopamine tone and attenuating the pro-inflammatory response via reduction in CRP. This can have an important role in improving the insulin resistance and other outcome of diabetes. Further investigations required to determine the exact role of prolactin in diabetes. KEY WORDS: Type II diabetes mellitus, prolactin, C-reactive protein, metformin.
... bovis were related with the production of NO, pro-inflammatory cytokines (IL-β, IL-6, and TNF-α), and anti-inflammatory cytokines (IL-10), because the secretion of these cytokines was inhibited using primary antibodies. In a previous report, in other models, activation of monocytes with both LPS and high concentrations of PRL mimics physiological hyperprolactinemic states, such as during pregnancy, promoting proinflammatory responses via nuclear factor-kappa beta (NF-κΒ) and IRF-1, as well as IL-10 release (Brand et al., 2004). In pregnant women, it was demonstrated that PRL regulates proinflammatory cytokine expression at the fetomaternal interface in first-trimester miscarriage (Garzia et al., 2013). ...
... In addition, they have proven that significantly higher levels of total cholesterol, LDL cholesterol and apolipoprotein B can be noted in patients with prolactinomas when compared with the results of the control group of healthy respondents. Some studies indicate that endothelial dysfunction and low-grade inflammation in patients with hyperprolactinemia were reversible after using the treatment with bromocriptine [6,[10][11][12]. ...
Article
Prolactin is a metabolic hormone. The hypothesis is that hyperprolactinemia can cause metabolic and inflammatory changes which are associated with accelerated atherosclerotic process, but the treatment of hyperprolactinemia with dopamine agonists, leads to reversibility of these processes. The first aim of this study was to determine whether hyperprolactinemia in premenopausal women is accompanied with the increase in body mass index (BMI), changes in body composition, lipid disturbances, the presence of inflammation and changes in systolic and diastolic blood pressure as risk factors for the development of early atherosclerosis. The second aim was to know whether the therapy of hyperprolactinemia and prolactin normalization lead to improvement of the observed parameters. Twenty female patients with prolactinomas, before and during treatment with dopamine agonists and 16 healthy controls were evaluated. Prolactin, BMI, total body fat, free fat mass, total body water, total cholesterol, triglycerides, high density lipoprotein (HDL), low density lipoprotein (LDL) and fibrinogen as well as systolic and diastolic blood pressure were measured at baseline and during the therapy. Hyperprolactinemic patients had pathologic and significantly higher levels of prolactin (PRL) than the controls (p=0.000). The BMI, body fat, total body water (TBW), total cholesterol, triglycerides, LDL were in normal range and higher in the patients than in the controls. HDL was lower in hyperprolactinemic females than controls. The difference was significant only for body fat (fat % p=0.006; fat kg p=0.009). Fibrinogen was slightly increased in patients compared with the controls. Hyperprolactinemic patients had normal, but increased levels of systolic and diastolic blood pressure compared with the controls. The difference with border significance was found in diastolic blood pressure (p=0.065). The correlation of PRL with all the observed parameters was positive apart from HDL, but relatively significant only with diastolic blood pressure (r=0.31). The therapy with dopamine agonists caused the decrease of all the observed parameters, but significant decreases was achieved only in BMI (p=0.028), total cholesterol levels (p<0.001) and LDL (p<0.002). Changes in BMI, body composition, serum lipids and lipoproteins, fibrinogen level and blood pressure confirm our hypothesis about the possible role of hyperprolactinemia in developing adverse metabolic disturbances which are reversible after treatment. Copyright © 2015 Elsevier Ltd. All rights reserved.
... PRL is secreted by the pituitary gland and its elevated concentration in serum correlates with abnormalities in immune response [41]. The physiological importance of PRL is not fully known, but some suggested it maybe a regulator of stress response [42]. ...
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Introduction: The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important. Methods: Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of APOE e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE). Results: Seven proteins were significantly associated with Aβ1-42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD. Discussion: Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, others' roles in symptomatic AD samples worth further explorations.
... The immunomodulatory activities of PRL may arise from increasing nuclear transcription factors such as IRF-1 and NFkB, which play a pivotal role in many immune functions and pathophysiological processes in physiological hyperprolactinemic states (e.g. pregnancy) [17]. However, PRL is known to have other contradictory actions on the immune system that depend upon the concentration (e.g. it can inhibit lymphocyte proliferation at high concentrations, while it enhances proliferation at lower concentrations [79,80,87]. ...
Article
Prolactin (PRL) is a peptide hormone produced by the pituitary gland and diverse extrapituitary sites, which triggers activation of various signaling pathways after binding to its receptor (PRLr) resulting in the activation of specific genes associated with the pleiotropic activities of PLR. To date, various PRLr isoforms have been described, generated by post-transcriptional or post-translational processes. PRL has been associated with the modulation of a variety of actions in the immune response and inflammatory processes in several physiologic and pathologic conditions. However, PRL can have opposite effects, which might be regulated by interaction with the various isoforms of PRLR and PRL variants, as well as the cellular and molecular microenvironment influence.
... In the lung, dopamine receptors are known to directly control alveolar cell inflammatory processes, and indirectly via parathyroid hormone and prolactin release (40,41). Prolactin promotes proinflammatory innate immune responses via NF-kB and IRF-1 (42). We found decreased expression of dopamine receptor signaling and the downstream pathways (parathyroid hormone, prolactin, and IRIF-1) in TB cavity wall. ...
Article
Rationale: There is poor understanding about protective immunity and the pathogenesis of cavitation in patients with tuberculosis.Objectives: To map pathophysiological pathways at anatomically distinct positions within the human tuberculosis cavity.Methods: Biopsies were obtained from eight predetermined locations within lung cavities of patients with multidrug-resistant tuberculosis undergoing therapeutic surgical resection (n = 14) and healthy lung tissue from control subjects without tuberculosis (n = 10). RNA sequencing, immunohistochemistry, and bacterial load determination were performed at each cavity position. Differentially expressed genes were normalized to control subjects without tuberculosis, and ontologically mapped to identify a spatially compartmentalized pathophysiological map of the cavity. In silico perturbation using a novel distance-dependent dynamical sink model was used to investigate interactions between immune networks and bacterial burden, and to integrate these identified pathways.Measurements and Main Results: The median (range) lung cavity volume on positron emission tomography/computed tomography scans was 50 cm3 (15-389 cm3). RNA sequence reads (31% splice variants) mapped to 19,049 annotated human genes. Multiple proinflammatory pathways were upregulated in the cavity wall, whereas a downregulation "sink" in the central caseum-fluid interface characterized 53% of pathways including neuroendocrine signaling, calcium signaling, triggering receptor expressed on myeloid cells-1, reactive oxygen and nitrogen species production, retinoic acid-mediated apoptosis, and RIG-I-like receptor signaling. The mathematical model demonstrated that neuroendocrine, protein kinase C-θ, and triggering receptor expressed on myeloid cells-1 pathways, and macrophage and neutrophil numbers, had the highest correlation with bacterial burden (r > 0.6), whereas T-helper effector systems did not.Conclusions: These data provide novel insights into host immunity to Mycobacterium tuberculosis-related cavitation. The pathways defined may serve as useful targets for the design of host-directed therapies, and transmission prevention interventions.
... Prolactin has been clearly linked to mammary gland growth (Svennersten-Sjaunja and Olsson, 2005) and long days increase circulating levels of prolactin, including the peripartum surge of this hormone (Newbold et al., 1991). However, not less important are the functions of prolactin related to its role in regulating immune system actions (Kooijman et al., 1996;Brand et al., 2004) and thus its role in favouring the gestation period. In fact, photoperiod may influence immunocompetence (Bilbo et al., 2002;Prendergast et al., 2002). ...
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The seasonality of reproduction in most mammals is dictated by photoperiod, temperature and nutrition. Melatonin, mainly synthesized in the pineal gland, is generally accepted as the active mediator of photoperiod responses including reproduction. While non-pregnant heifers and cows show continuous sexual activity and are therefore not seasonal breeders, it has been suggested that photo-periodicity may influence the appearance of puberty in heifers and the onset of parturition. Further, the light/dark ratio may influence endocrine patterns of gestation and a shorter light period correlates with the incidence of twin pregnancies. This review considers specific aspects of the effects of photoperiod and melatonin on reproduction in dairy cattle and discusses the clinical applications of melatonin.
... The mechanism is that miR-363-3p can inhibit the activity of PI3K-AKT signaling pathway by down-regulating the expression of integrin subunit alpha 6 (ITGA6) [11]. Prolactin (PRL) gene is located on chromosome 6, closely to HLA-DRB1 region, which is associated with a variety of immune-mediated diseases [12]. Thioesterase superfamily member 4 (THEM4) negatively regulates the activity of AKT by inhibiting phosphorylation, inhibits the activity of PI3K-AKT signaling pathway, and promotes cell proliferation and migration [13]. ...
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Purpose Autoimmune thyroiditis (AIT) is one of the most common autoimmune endocrine diseases. The currently recognized causes are genetic susceptibility, environmental factors and immune disorders. It is important to clarify the pathogenesis for the prevention, diagnosis, treatment of AIT and scientific iodine supplementation. This study analyzed the DNA methylation levels of PRKAA2, ITGA6, PRL and THEM4 genes related to PI3K-AKT signaling pathway, compared the DNA methylation levels between cases and controls from different water iodine levels in Shandong Province of China, and evaluated the contribution of PI3K-AKT signaling pathway-related genes in AIT. Methods A total of 176 adult AIT patients were included from three different water iodine areas, and 176 healthy controls were included according to gender, age and BMI. According to the results of the Illumina Methylation 850 K BeadChip in our previous research, the significant methylation differences of genes on the PI3K-AKT signaling pathway related to AIT were determined. The MethylTarget™ assay was used to detect the methylation levels of the target genes, and real-time PCR experiments were used to verify the mRNA expression levels. Results Compared with the control group, PRKAA2_3 and 15 CpG sites were hyper-methylated. ITGA6 gene and 2 CpG sites were hypo-methylated in AIT cases. The mRNA expression of ITGA6 gene was negatively correlated with the DNA methylation levels of ITGA6 gene and 2 CpG sites. Compared with cases and controls in areas with different water iodine levels, methylation differences were mainly in PRKAA2 and ITGA6 genes. The methylation levels of PRKAA2_1 and PRKAA2_3 were positively correlated with age. The methylation levels of PRL and THEM4 genes were negatively correlated with age. The methylation level of PRKAA2_3 was positively correlated with FT4. Conclusion In summary, we identified aberrant DNA methylation levels of PRKAA2 and ITGA6 genes related to PI3K-AKT signaling pathway in the blood of AIT patients. Both iodine supplementation after long-term iodine deficiency and iodine excess can affect the DNA methylation levels of PRKAA2 and ITGA6 genes, and the former affects more obviously. In ITGA6 gene, this aberrant epigenetic modification is associated with the increased mRNA expression.
... A direct association between PRL serum level and CD4+ T lymphocytes has been clarified by induction expression of NF-κB and IRF-1 [33]. Likewise, high PRL serum level and hyperprolactinemia promote auto-reactivity by inhibiting B cells clonal deletion and alteration activation threshold and tolerance for B cells [34]. ...
Article
Prolactin (PRL) is a peptide hormone secreted from anterior pituitary involved in milk production in the females and regulation of sex drive in both sexes. PRL has pro-inflammatory and anti-inflammatory functions. High PRL serum level or hyperprolactinemia is associated with different viral infections. In coronavirus disease 2019 (Covid-19), which caused by positive-sense single-strand RNA virus known as severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2), PRL serum level is increased. PRL in Covid-19 may exacerbate the underlying inflammatory status by induction release of pro-inflammatory cytokines. However, PRL through its anti-inflammatory effects may reduce the hyperinflammatory status in Covid-19. The underlying mechanism of increasing PRL in Covid-19 is poorly understood. Therefore, in this review we try to find the potential anti-inflammatory or pro-inflammatory role of PRL in Covid-19. As well, this review was aimed to discuss the underlying causes and mechanisms for Covid-19-induced hyperprolactinemia.
... A direct association between PRL serum level and CD4+ T lymphocytes has been clarified by induction expression of NF-κB and IRF-1 [33]. Likewise, high PRL serum level and hyperprolactinemia promote auto-reactivity by inhibiting B cells clonal deletion and alteration activation threshold and tolerance for B cells [34]. ...
Article
Full-text available
Prolactin (PRL) is a peptide hormone secreted from anterior pituitary involved in milk production in the females and regulation of sex drive in both sexes. PRL has pro-inflammatory and anti-inflammatory functions. High PRL serum level or hyperprolactinemia is associated with different viral infections. In coronavirus disease 2019 (Covid-19), which caused by positive-sense single-strand RNA virus known as severe acute respiratory distress syndrome coronavirus type 2 (SARS-CoV-2), PRL serum level is increased. PRL in Covid-19 may exacerbate the underlying inflammatory status by induction release of pro-inflammatory cytokines. However, PRL through its anti-inflammatory effects may reduce the hyperinflamma-tory status in Covid-19. The underlying mechanism of increasing PRL in Covid-19 is poorly understood. Therefore, in this review we try to find the potential anti-inflammatory or pro-inflammatory role of PRL in Covid-19. As well, this review was aimed to discuss the underlying causes and mechanisms for Covid-19-induced hyperprolactinemia.
... Both cortisol and PRL also contribute to the immune responses of cows. Prolactin enhances proliferation and triggers proinflammatory responses of peripheral lymphocytes (Auchtung and Dahl, 2004;Brand et al., 2004;Díaz et al., 2013). In contrast, cortisol exerts antiproliferative and anti-inflammatory effects on peripheral immune cells (Ashwell et al., 2000;Coutinho and Chapman, 2011). ...
Article
The aim of this trial was to evaluate the effects of an immunomodulatory supplement (OmniGen AF, OG; Phibro Animal Health Corp.) and heat stress on hormonal, inflammatory, and immunological responses of lactating dairy cows. Sixty multiparous Holstein cows were randomly assigned to 4 treatments in a 2 × 2 factorial arrangement using 2 environments: cooled using fans and misters, or noncooled, and 2 top-dressed feed supplements (56 g/d): OG or a placebo (CTL). Temperature-humidity index averaged 78 during the 8-wk trial. Blood was drawn to analyze cortisol, prolactin, and circulating tumor necrosis factor (TNF)-α and IL10. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated with hydrocortisone, prolactin, or lipopolysaccharide (LPS), individually or in several combinations, to assess induced proliferation and cytokine production. At d 52, 6 cows per treatment were injected i.v. with an LPS bolus (ivLPS) to assess hormone and cytokine responses. For cooled cows, feeding OG increased plasma cortisol concentration relative to CTL. Noncooled cows fed CTL had lower circulating TNF-α concentrations than noncooled-OG and cooled-CTL cows, with cooled-OG intermediate. Hydrocortisone+LPS-stimulated PBMC from OG cows tended to proliferate more than CTL. Relative to cooled cows, PBMC from noncooled cows produced more TNF-α and IL10 when stimulated with LPS. Following ivLPS, cooled-OG cows had a greater cortisol response than the other treatments. In conclusion, OG supplementation enhanced cortisol release under basal condition and induced inflammation with cooling compared with CTL. This suggests that heat stress inhibits OG-mediated cortisol release. Heat stress seemed to enhance the inflammatory responses of PBMC from lactating cows. However, OG supplementation promoted PBMC proliferation under stress, or in the presence of hydrocortisone.
... It has previously been reported that conditions of hypoprolactinemia and hyperprolactinemia usually produce anti-inflammatory and immunosuppressive effects, respectively. By contrast, increased PRL in physiological ranges favors inflammation and activation of the immune system (Brand et al. 2004;Matera 1997). Low concentrations of PLR (15-30 ng/ml) favor the secretion of cytokines such as IL-12 and IFN-γ in whole blood cells, but high concentrations (100-300 ng/ml) do not affect the secretion of these cytokines (Matalka 2003). ...
Article
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Prolactin has been shown to favor both the activation and suppression of the microglia and astrocytes, as well as the release of inflammatory and anti-inflammatory cytokines. Prolactin has also been associated with neuronal damage in diseases such as multiple sclerosis, epilepsy, and in experimental models of these diseases. However, studies show that prolactin has neuroprotective effects in conditions of neuronal damage and inflammation and may be used as neuroprotector factor. In this review, we first discuss general information about prolactin, then we summarize recent findings of prolactin function in inflammatory and anti-inflammatory processes and factors involved in the possible dual role of prolactin are described. Finally, we review the function of prolactin specifically in the central nervous system and how it promotes a neuroprotective effect, or that of neuronal damage, particularly in experimental autoimmune encephalomyelitis and during excitotoxicity. The overall studies indicated that prolactin may be a promising molecule for the treatment of some neurological diseases.
... Dopamine is the main regulator of prolactin, negatively controlling its synthesis and secretion in pituitary lactotrophs [65]. As we found here, microglial activity does not affect the pattern of prolactin secretion during sepsis, which may be beneficial, since this hormone has proinflammatory properties in many immune cells [66,67]. ...
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Sepsis promotes an inflammatory state in the central nervous system (CNS) that may cause autonomic, cognitive, and endocrine changes. Microglia, a resident immune cell of the CNS, is activated in several brain regions during sepsis, suggesting its participation in the central alterations observed in this disease. In this study, we aimed to investigate the role of microglial activation in the neuroendocrine system functions during systemic inflammation. Wistar rats received an intracerebroventricular injection of the microglial activation inhibitor minocycline (100 μg/animal), shortly before sepsis induction by cecal ligation and puncture. At 6 and 24 h after surgery, hormonal parameters, central and peripheral inflammation, and markers of apoptosis and synaptic function in the hypothalamus were analyzed. The administration of minocycline decreased the production of inflammatory mediators and the expression of cell death markers, especially in the late phase of sepsis (24 h). With respect to the endocrine parameters, microglial inhibition caused a decrease in oxytocin and an increase in corticosterone and vasopressin plasma levels in the early phase of sepsis (6 h), while in the late phase, we observed decreased oxytocin and increased ACTH and corticosterone levels compared to septic animals that did not receive minocycline. Prolactin levels were not affected by minocycline administration. The results indicate that microglial activation differentially modulates the secretion of several hormones and that this process is associated with inflammatory mediators produced both centrally and peripherally.
... Dopamine is the main regulator of prolactin, negatively controlling its synthesis and secretion in pituitary lactotrophs [65]. As we found here, microglial activity does not affect the pattern of prolactin secretion during sepsis, which may be beneficial, since this hormone has proinflammatory properties in many immune cells [66,67]. ...
Article
The absence of a specific treatment for SARS-CoV-2 infection led to an intense global effort in order to find new therapeutic interventions and improve patient outcomes. One important feature of COVID-19 pathophysiology is the activation of immune cells, with consequent massive production and release of inflammatory mediators that may cause impairment of several organ functions, including the brain. In addition to its classical role as a neurotransmitter, serotonin (5-hydroxytryptamine, 5-HT) has immunomodulatory properties, downregulating the inflammatory response by central and peripheral mechanisms. In this review, we describe the roles of 5-HT in the regulation of systemic inflammation and the potential benefits of the use of specific serotonin reuptake inhibitors as a coadjutant therapy to attenuate neurological complications of COVID-19.
... PRL sequences have since been isolated from a range of fish species including fugu, rainbow trout, European eel, Atlantic salmon, blue gourami, and starry flounder (Mercier et al., 1989;Querat et al., 1994;Martin et al., 1999;Lee et al., 2006;Degani et al., 2010;Noh et al., 2012), through which various physiological functions have been described. From an immunological point of view, PRL strongly persuades the innate and adaptive immune responses and a direct correlation between PRL levels and the number of B and CD4 + T lymphocytes was previously reported (Brand et al., 2004). Furthermore, PRL increases Ig production, stimulates the development of antigen-presenting cells expressing the major histocompatibility complex class II, and upholds the co-stimulatory molecules CD86, CD80, and CD40 (Peeva and Zouali, 2005). ...
Article
Prolactin has several immune functions in fish however, the effects on innate and specific components of rainbow trout immunity are currently unknown. Therefore in this study, prolactin peptide (pPRL) injection in rainbow trout generated anti-PRL antibodies that were confirmed through Western blot assays of fish brain tissue extract. At the same time, this group of fish was immunized with a viral antigen (VP2) and the specific antibody titer generated by the rainbow trout was subsequently determined, as well as the sero-neutralizing capacity of the antibodies. Interestingly, this group of fish (pPRL-VP2) generated approximately 150% less antibodies compared with fish immunized only with the viral antigen (VP2), and pPRL-VP2 fish increased their cortisol level by 4 times compared to the control. Additionally, through qPCR assay, we determined that the pPRL-VP2 fish group decreased pro-inflammatory transcript expression, and the serum of these (pPRL-VP2) fish stimulated ROS production in untreated fish leukocytes, a phenomenon that was blocked by the pharmacological cortisol receptor inhibitor (RU486). Collectively, this is the first report that indicates that pPRL could modulate both components of immunity in rainbow trout.
... In the current study, greater symptom burden and recovery time were associated with lower DHEA-S and progesterone; progesterone may limit oxidative stress following TBI, while DHEA-S and progesterone have both been associated with reducing neuroinflammation 30,37 . In addition, we observed that higher levels of prolactin -a potential proinflammatory mediator -were related to increased time to recovery and cognitive symptom reporting 60,61 . Hence, the relationship between an unfavorable clinical profile (symptom reporting and time to medical clearance), lower levels of hormones theorized to reduce inflammation and oxidative stress (DHEA-S and progesterone), and higher levels of a proinflammatory-associated hormone (prolactin) are consistent with our previous works and support a role for the neuroendocrine system in multiple facets of secondary injury. ...
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The purpose of this study was to evaluate the relationship between neuroendocrine hormones and clinical recovery following sport-related concussion (SRC). Ninety-five athletes (n = 56 male, n = 39 female) from a cohort of 11 interuniversity sport teams at a single institution provided blood samples; twenty six athletes with SRC were recruited 2–7 days post-injury, and 69 uninjured athletes recruited prior to the start of their competitive season. Concentrations of seven neuroendocrine hormones were quantitated in either plasma or serum by solid-phase chemiluminescent immunoassay. The Sport Concussion Assessment Tool version 5 (SCAT-5) was used to evaluate symptoms at the time of blood sampling in all athletes. Multivariate partial least squares (PLS) analyses were used to evaluate the relationship between blood hormone concentrations and both (1) time to physician medical clearance and (2) initial symptom burden. A negative relationship was observed between time to medical clearance and both dehydroepiandrosterone sulfate (DHEA-S) and progesterone; a positive relationship was found between time to medical clearance and prolactin. Cognitive, somatic, fatigue and emotion symptom clusters were associated with distinct neuroendocrine signatures. Perturbations to the neuroendocrine system in athletes following SRC may contribute to initial symptom burden and longer recovery times.
Article
Recent studies support the hypothesis that the adverse effects of early-life adversity and transgenerational stress on neural plasticity and behavior are mediated by inflammation. The objective of the present study was to investigate the immune and behavioral programing effects of intranasal (IN) vasopressin (AVP) and oxytocin (OXT) treatment of chronic social stress (CSS)-exposed F1 dams on F2 juvenile female offspring. It was hypothesized that maternal AVP and OXT treatment would have preventative effects on social stress-induced deficits in offspring anxiety and social behavior and that these effects would be associated with changes in interferon-γ (IFNγ). Control and CSS-exposed F1 dams were administered IN saline, AVP, or OXT during lactation and the F2 juvenile female offspring were assessed for basal plasma IFNγ and perseverative, anxiety, and social behavior. CSS F2 female juvenile offspring had elevated IFNγ levels and exhibited increased repetitive/perseverative and anxiety behaviors and deficits in social behavior. These effects were modulated by AVP and OXT in a context- and behavior-dependent manner, with OXT exhibiting preventative effects on repetitive and anxiety behaviors and AVP possessing preventative effects on social behavior deficits and anxiety. Basal IFNγ levels were elevated in the F2 offspring of OXT-treated F1 dams, but IFNγ was not correlated with the behavioral effects. These results support the hypothesis that maternal AVP and OXT treatment have context- and behavior-specific effects on peripheral IFNγ levels and perseverative, anxiety, and social behaviors in the female offspring of early-life social stress-exposed dams. Both maternal AVP and OXT are effective at preventing social stress-induced increases in self-directed measures of anxiety, and AVP is particularly effective at preventing impairments in overall social contact. OXT is specifically effective at preventing repetitive/perseverative behaviors, yet is ineffective at preventing deficits in overall social behavior.
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Limited work exists for the comparison across distinct knowledge-based approaches in Artificial Intelligence (AI) for non-monotonic reasoning, and in particular for the examination of their inferential and explanatory capacity. Non-monotonicity, or defeasibility, allows the retraction of a conclusion in the light of new information. It is a similar pattern to human reasoning, which draws conclusions in the absence of information, but allows them to be corrected once new pieces of evidence arise. Thus, this thesis focuses on a comparison of three approaches in AI for implementation of non-monotonic reasoning models of inference, namely: expert systems, fuzzy reasoning and defeasible argumentation. Three applications from the fields of decision-making in healthcare and knowledge representation and reasoning were selected from real-world contexts for evaluation: human mental workload modelling, computational trust modelling, and mortality occurrence modelling with biomarkers. The link between these applications comes from their presumptively non-monotonic nature. They present incomplete, ambiguous and retractable pieces of evidence. Hence, reasoning applied to them is likely suitable for being modelled by non-monotonic reasoning systems. An experiment was performed by exploiting six deductive knowledge bases produced with the aid of domain experts. These were coded into models built upon the selected reasoning approaches and were subsequently elicited with real-world data. The numerical inferences produced by these models were analysed according to common metrics of evaluation for each field of application. For the examination of explanatory capacity, properties such as understandability, extensibility, and post-hoc interpretability were meticulously described and qualitatively compared. Findings suggest that the variance of the inferences produced by expert systems and fuzzy reasoning models was higher, highlighting poor stability. In contrast, the variance of argument-based models was lower, showing a superior stability of its inferences across different system configurations. In addition, when compared in a context with large amounts of conflicting information, defeasible argumentation exhibited a stronger potential for conflict resolution, while presenting robust inferences. An in-depth discussion of the explanatory capacity showed how defeasible argumentation can lead to the construction of non-monotonic models with appealing properties of explainability, compared to those built with expert systems and fuzzy reasoning. The originality of this research lies in the quantification of the impact of defeasible argumentation. It illustrates the construction of an extensive number of non-monotonic reasoning models through a modular design. In addition, it exemplifies how these models can be exploited for performing non-monotonic reasoning and producing quantitative inferences in real-world applications. It contributes to the field of non-monotonic reasoning by situating defeasible argumentation among similar approaches through a novel empirical comparison.
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Objectives Patients with type 1 diabetes mellitus have been reported to have elevated prolactin levels and a possible relationship between prolactin levels and the development of the disease has been proposed. However, some studies show that prolactin mediates beneficial functions in beta cells. Therefore, we review information on the roles of prolactin in type 1 diabetes mellitus. Content Here we summarize the functions of prolactin in the immune system and in pancreatic beta cells, in addition, we describe studies related to PRL levels, its regulation and alterations of secretion in patients with type 1 diabetes mellitus. Summary Studies in murine models have shown that prolactin protects beta cells from apoptosis, stimulates their proliferation and promotes pancreatic islet revascularization. In addition, some studies in patients with type 1 diabetes mellitus have shown that elevated prolactin levels correlate with better disease control. Outlook Prolactin treatment appears to be a promising strategy to improve beta-cell vascularization and proliferation in transplantation and immunotherapies.
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Evidence exists about the relationship between the immune and the endocrine systems through communication of multiple factors such as cytokines, neuropeptides, neurotransmitters and hormones. Among the hormones, prolactin (PRL) has been shown to participate in the innate and adaptive immune response. In addition to being produced by the pituitary gland, PRL is also produced and secreted by cells of the immune system. The aim of this review is to update information about the involvement of PRL secreted by immune system cells in the immune response.
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Cognitive deficits are a core feature of serious mental illnesses such as major depression, bipolar disorder and schizophrenia and are a common cause of functional disability. However, the efficacy of pharmacological interventions for improving the cognitive deficits in these disorders is limited. As pro-cognitive pharmacological treatments are lacking, we aimed to review whether thyroid hormones or drugs that target prolactin may become potential candidates for ‘repurposing’ trials aiming to improve cognition. We conducted a narrative review focused on thyroid hormones and prolactin as potential targets for improving cognition in major mood disorders or schizophrenia. The role of thyroid hormones and prolactin on cognitive processes in non-psychiatric populations was also reviewed. Although clinical trials regarding these hormones are lacking, particularly in patients with schizophrenia, bipolar disorder or major depression, there is evidence from observational studies for the contribution of these hormones to cognitive processes. Patients with bipolar disorder and subclinical hypothyroidism show poorer cognitive function than euthyroid patients. In patients with early psychosis, lower free thyroxine concentrations have been associated with poorer attention whereas increased prolactin levels have been associated with poorer speed of processing. Only two small clinical trials tested the potential pro-cognitive effects of thyroid hormones, with positive findings for triiodothyronine (T3) treatment in patients receiving lithium or electroconvulsive therapy. In sum, thyroid hormones and prolactin might contribute to the cognitive performance of patients with major mood disorders and psychotic disorders. Thyroid hormones and prolactin-lowering drugs (e.g. cabergoline, aripiprazole) are candidate drugs to be tested in repurposing clinical trials aiming to improve the cognitive abilities of patients with major mood disorder and schizophrenia.
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Nowadays, more than 80 autoimmune disorders are recognized, in which an aberrant immune response against different organs and tissues plays a crucial role. Hormonal homeostasis has great influence in achieving competent and healthy immune system function. Prolactin has a bioactive function acting as a hormone and a cytokine. It influences the immune system modulation, mainly inhibiting the negative selection of autoreactive B lymphocytes. Hyperprolactinemia has been detected in many patients with different autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, multiple sclerosis, autoimmune thyroid disease, systemic sclerosis, among others, and its believed to play a crucial role in disease pathogenesis. A direct correlation between prolactin levels and disease activity was not clear. Genetic factors may have a role in humans as in animal models. Dopamine agonists have proven to offer clinical benefits among autoimmune patients and represent a promising therapy to be explored. In this review, the authors attempt to provide a critical overview on the role of prolactin in the immune system, exploring its contribution to the development of autoimmune diseases.
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Objective Migraine is three times more common in women. CGRP plays a critical role in migraine pathology and causes female‐specific behavioral responses upon meningeal application. These effects are likely mediated through interactions of CGRP with signaling systems specific to females. Prolactin (PRL) levels have been correlated with migraine attacks. Here, we explore a potential interaction between CGRP and PRL in the meninges. Methods Prolactin, CGRP, and receptor antagonists CGRP8‐37 or Δ1‐9‐G129R‐hPRL were administered onto the dura of rodents followed by behavioral testing. Immunohistochemistry was used to examine PRL, CGRP and Prolactin receptor (Prlr) expression within the dura. Electrophysiology on cultured and back‐labeled trigeminal ganglia (TG) neurons was used to assess PRL‐induced excitability. Finally, the effects of PRL on evoked CGRP release from ex vivo dura were measured. Results We found that dural PRL produced sustained and long‐lasting migraine‐like behavior in cycling and ovariectomized female, but not male rodents. Prlr was expressed on dural afferent nerves in females with little‐to‐no presence in males. Consistent with this, PRL increased excitability only in female TG neurons innervating the dura and selectively sensitized CGRP release from female ex vivo dura. We demonstrate crosstalk between PRL and CGRP systems as CGRP8‐37 decreases migraine‐like responses to dural PRL. Reciprocally, Δ1‐9‐G129R‐hPRL attenuates dural CGRP‐induced migraine behaviors. Similarly, Prlr deletion from sensory neurons significantly reduced migraine‐like responses to dural CGRP. Interpretation This CGRP‐PRL interaction in the meninges is a mechanism by which these peptides could produce female‐selective responses and increase the prevalence of migraine in women. This article is protected by copyright. All rights reserved.
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Autoimmune diseases represent a complex heterogeneous group of disorders that occur as a results of immune homeostasis dysregulation and loss of self-tolerance. Interestingly, more than 80% of the cases are found among women at reproductive age. Normal pregnancy is associated with remarkable changes in the immune and endocrine signaling required to tolerate and support the development and survival of the placenta and the semi-allogenic fetus in the hostile maternal immune system environment. Gravidity and postpartum represent an extremely challenge period, and likewise the general population, women suffering from autoimmune disorders attempt pregnancy. Effective preconception counseling and subsequent gestation and postpartum follow-up are crucial for improving mother and child outcomes. This comprehensive review provides information about the different pathways modulating autoimmune diseases activity and severity, such as the influence hormones, microbiome, infections, vaccines, among others, as well as updated recommendations were needed, in order to offer those women better medical care and life quality.
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Background: Prenatal alcohol exposure (PAE) is associated with alterations in numerous physiological systems, including the stress and immune systems. We have previously shown that PAE increases the course and severity of arthritis in an adjuvant-induced arthritis (AA) model. While the molecular mechanisms underlying these effects are not fully known, changes in neural gene expression are emerging as important factors in the etiology of PAE effects. As the prefrontal cortex (PFC) and hippocampus (HPC) play key roles in neuroimmune function, PAE-induced alterations to their transcriptome may underlie abnormal steady-state functions and responses to immune challenge. This study examined brains from adult PAE and control females from our recent AA study to determine whether PAE causes long-term alterations in gene expression and whether these mediate the altered severity and course of arthritis in PAE females. Methods: Adult females from PAE, pair-fed (PF), and ad libitum-fed control (C) groups were injected with either saline or complete Freund's adjuvant. Animals were terminated at the peak of inflammation or during resolution (Days 16 and 39 postinjection, respectively); cohorts of saline-injected PAE, PF, and C females were terminated in parallel. Gene expression was analyzed in the PFC and HPC using whole-genome mRNA expression microarrays. Results: Significant changes in gene expression in both the PFC and HPC were found in PAE compared to controls in response to ethanol exposure alone (saline-injected females), including genes involved in neurodevelopment, apoptosis, and energy metabolism. Moreover, in response to inflammation (adjuvant-injected females), PAE animals showed unique expression patterns, while failing to exhibit the activation of genes and regulators involved in the immune response observed in control and pair-fed animals. Conclusions: These results support the hypothesis that PAE affects neuroimmune function at the level of gene expression, demonstrating long-term effects of PAE on the central nervous system response under steady-state conditions and following an inflammatory insult.
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Recurrent miscarriage which is seen in 1–5% of couples is unexplained in approximately half of them. Stress as a possible cause of miscarriage has now been elucidated in detail with several studies reporting it as an etiological factor in recurrent miscarriage. The pathophysiological changes in response to stress involve a complex interaction between the neuroendocrine and immune systems. This chapter describes the pathophysiology and evidence regarding the role of stress in recurrent miscarriage.
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Hypophysectomized (Hypo-X) rats do not develop contact sensitivity to dinitrochlorobenzene (DNCB). Daily treatment with prolactin or growth hormone completely restores the DNCB-reactivity of Hypo-X animals. Treatment of such animals with ACTH, FSH, LH, TSH or HCG has no restoring potential. Treatment with ACTH in addition to prolactin or growth hormone antagonizes restoration of Hypo-X rats. These experiments indicate that the pituitary gland has the potential of regulating contact sensitivity.
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Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.
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IL-12 and IFN-gamma positively regulate each other and type 1 inflammatory responses, which are believed to cause tissue damage in autoimmune diseases. We investigated the role of the IL-12/IFN-gamma (Th1) axis in the development of autoimmune myocarditis. IL-12p40-deficient mice on a susceptible background resisted myocarditis. In the absence of IL-12, autospecific CD4(+) T cells proliferated poorly and showed increased Th2 cytokine responses. However, IFN-gamma-deficient mice developed fatal autoimmune disease, and blockade of IL-4R signaling did not confer susceptibility to myocarditis in IL-12p40-deficient mice, demonstrating that IL-12 triggers autoimmunity by a mechanism independent of the effector cytokines IFN-gamma and IL-4. In conclusion, our results suggest that the IL-12/IFN-gamma axis is a double-edged sword for the development of autoimmune myocarditis. Although IL-12 mediates disease by induction/expansion of Th1-type cells, IFN-gamma production from these cells limits disease progression.
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Signal transducers and activators of transcription (Stat) are latent transcription factors that participate in cytokine signaling by regulating the expression of early response genes. Our previous studies showed that Stat5 functions not only as a transcriptional activator but also as a transcriptional inhibitor, depending on the target promoter. This report further investigates the mechanism of Stat5b-mediated inhibition and demonstrates that PRL-inducible Stat5b inhibits nuclear factor kappa B (NF kappa B) signaling to both the interferon regulatory factor-1 promoter and to the thymidine kinase promoter containing multimerized NF kappa B elements (NF kappa B-TK). Further, PRL-inducible Stat5b inhibits tumor necrosis factor-alpha signaling presumably by inhibiting endogenous NF kappa B. tThis Stat5b-mediated inhibitory effect on NF kappa B signaling is independent of Stat5b-DNA interactions but requires the carboxyl terminus of Stat5b as well as Stat5b nuclear translocation and/or accumulation, suggesting that Stat5b is competing for a nuclear factor(s) necessary for NF kappa B-mediated activation of target promoters. Increasing concentrations of the coactivator p300/CBP reverses Stat5b inhibition at both the interferon-regulatory factor-1 and NF kappa B-TK promoters, suggesting that Stat5b may be squelching limiting coactivators via protein-protein interactions as one mechanism of promoter inhibition. These results further substantiate our observation that Stat factors can function as transcriptional inhibitors. Our studies reveal cross-talk between the Stat5b and NF kappa B signal transduction pathways and suggest that Stat5b-mediated inhibition of target promoters occurs at the level of protein-protein interactions and involves competition for limiting coactivators.
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Interleukin-12 (IL-12) is a cytokine composed of two chains, a heavy chain or p40, and a light chain or p35, forming a disulfite-linked heterodimer, or p70. IL-12 was originally discovered as a product of human B lymphoblastoid cell lines; however, the most important physiological producers of IL-12 in vitro are phagocytic cells and antigen-presenting cells rather than B cells. The major target cells of IL-12 action are natural killer and T cells, on which IL-12 induce: (1) production of cytokine, particularly interferon-gamma (IFN-gamma); (2) proliferation, in synergy with other mitogenic or costimulatory signals; (3) enhancement of cytotoxic activity. In addition, IL-12 has been described to have stimulatory effects on hematopoietic precursor cells and on B lymphocytes. In vivo, IL-12 is produced very early during infections or immune response, and exerts important proinflammatory functions and enhancement of innate resistance by activating natural killer cells and, through IFN-gamma induction, phagocytic cells. The IL-12 produced during this inflammatory phase, both by direct action and, indirectly, by determining the composition of the cytokine milieu at the site of the murine response, induces differentiation of T helper type 1 (Th1) cells while inhibiting the generation of Th2 cells. Thus, because of its double function of a proinflammatory cytokine and an immunoregulatory factor, IL-12 plays a key role in the resistance to infections, particularly those mediated by bacteria or intracellular parasites, against which phagocytic cell activation and Th1-mediated responses are particularly effective. However, because of the same activities, IL-12 also plays a role in pathological situations, such as septic shock, tissue damage during inflammation and organ-specific autoimmune diseases.
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Interferon production was studied in mixtures of whole blood of healthy adults with tissue culture medium. There was no need to supplement the system with additional foreign serum and even the autologous serum and even the autologous serum could be removed by washing in serum-free medium with-out impairment of interferon production. Heparinized blood samples could be stored in the refrigerator overnight before performing the assay. In this test, production of interferon gamma was observed in response to phytohemagglutinin, concanavalin A, pokeweed mitogen, staphylococcal enterotoxin A, and to OKT-3, a monoclonal anti-T cell antibody. Production of interferon alpha was observed when viruses were used as inducers. Our experiments show that in the whole-blood assay the responses to several inducers of different types of interferons may be readily monitored under serum-free conditions. We believe that this test will be of value for testing large numbers of normal individuals (for investigations of the genetics of interferon production) or of patients with a variety of diseases.
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In this study we examined the signalling events that regulate lipopolysaccharide (LPS)-stimulated induction of interferon regulatory factor (IRF)-1 in human umbilical vein endothelial cells (HUVECs). LPS stimulated a time- and concentration-dependent increase in IRF-1 protein expression, an effect that was mimicked by the cytokine, tumour necrosis factor (TNF)-α. LPS stimulated a rapid increase in nuclear factor kappa B (NFκB) DNA-binding activity. Pre-incubation with the NFκB pathway inhibitors, N-α-tosyl-L-lysine chloromethyl ketone (TLCK) or pyrrolidine dithiocarbamate (PDTC), or infection with adenovirus encoding IκBα, blocked both IRF-1 induction and NFκB DNA-binding activity. LPS and TNFα also stimulated a rapid activation of gamma interferon activation site/gamma interferon activation factor (GAS/GAF) DNA-binding in HUVECs. Preincubation with the Janus kinase (JAK)-2 inhibitor, AG490 blocked LPS-stimulated IRF-1 induction but did not affect GAS/GAF DNA-binding. Preincubation with TLCK, PDTC or infection with IκBα adenovirus abolished LPS-stimulated GAS/GAF DNA-binding. Incubation of nuclear extracts with antibodies to RelA/p50 supershifted GAS/GAF DNA-binding demonstrating the involvement of NFκB isoforms in the formation of the GAS/GAF complex. These studies show that NFκB plays an important role in the regulation of IRF-1 induction in HUVECs. This is in part due to the interaction of NFκB isoforms with the GAS/GAF complex either directly or via an intermediate protein. British Journal of Pharmacology (2001) 134, 1629–1638; doi:10.1038/sj.bjp.0704404
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The neuroendocrine and behavioral responses to the potent mu opiate receptor agonist Fentanyl (FE) have been systematically investigated in healthy male volunteers. These volunteers received, according to a randomized block design, different doses of FE: 0.1 mg/70 kg (n = 11), 0.2 mg/70 kg (n = 11), 0.25 mg/70 kg (n = 8), and saline (n = 11). FE induced a pronounced dose-dependent increase of plasma prolactin concentrations, which was significant at the lowest dose. In contrast, growth hormone was significantly stimulated by the highest FE dose only. Moreover, FE induced a maximum reduction of plasma cortisol concentrations at the lowest dose (0.1 mg/70 kg). In parallel, marked euphoric responses were also observed at this lowest FE dose. These results suggest a mu specific influence on all neuroendocrine and behavioral parameters investigated. Different responses of these parameters to different doses of FE, however, suggest a differential modulation of these parameters by the mu receptor agonist FE.
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This study was performed to establish the dynamics of human chorionic gonadotropin, prolactin, and growth hormone throughout pregnancy in serum and amniotic fluid. Two hundred fifty healthy women at 8 to 42 weeks' gestation were studied. The highest serum human chorionic gonadotropin level was measured between weeks 8 to 12 (53,715 +/- 3574 mIU/ml, mean +/- SEM), with a decline to a mean plateau of 11,806 +/- 1250 mIU/ml from week 18. Amniotic fluid human chorionic gonadotropin had a similar pattern with a mean of 68,100 +/- 8422 mIU/ml at weeks 8 to 10, declining from week 18 to a plateau of 2005 +/- 260 mIU/ml. Human chorionic gonadotropin showed a significant correlation (r = 0.85, p less than 0.001) between levels of both compartments demonstrating an even distribution. Prolactin levels showed a dichotomy of patterns and levels. Serum prolactin showed a continuous rise from 45.3 +/- 14 ng/ml at week 8 to 224 +/- 20 ng/ml at week 36. In contrast, amniotic fluid prolactin remained low until week 14 (33.1 +/- 0.8 ng/ml), followed by a sharp and significant (p less than 0.001) increase to a plateau of 3750 +/- 200 ng/ml between weeks 18 to 26, declining to a second plateau of 500 +/- 50 ng/ml at week 36. Serum growth hormone increased from a mean of 3.5 +/- 1.4 ng/ml seen at weeks 8 to 10 to a mean of 14 +/- 2.0 ng/ml at weeks 28 to 30, followed by a plateau of similar levels. The pattern of growth hormone secretion in amniotic fluid demonstrated a sharp increase during the 14-16 interval with a maximum mean level of 15.5 +/- 1.5 ng/ml and a slow steady decline thereafter. In conclusion, the similar pattern and concentration of human chorionic gonadotropin throughout pregnancy in both maternal and amniotic fluid are probably the result of direct human chorionic gonadotropin diffusion from the placenta. The dissimilar pattern and concentration of prolactin are the result of two different sources of prolactin secretion during pregnancy. Serum prolactin originates from the pituitary and amniotic fluid prolactin from the decidua. Since the pattern of growth hormone secretion resembles that of prolactin, it is possible that growth hormone, like prolactin, is secreted by the same sources.
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Antibody formation to sheep red blood cells and the development of contact dermatitis in response to dinitrochlorobenzene are impaired in hypophysectomized (Hypo-X) rats. Rat prolactin, rat growth hormone, bovine prolactin, bovine growth hormone, human placental lactogen and human growth hormone all restored the immunological competence of Hypo-X animals. The possible mechanism of action of these hormones on immune reactions is discussed.
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Distribution of transcripts for prolactin and growth hormone receptors (PRLR and GHR) and their isoforms was characterized in the gastrointestinal (GI) tract from several species by reverse transcription-polymerase chain reaction combined with Southern analysis. Human, rabbit, and fetal and adult rat PRLR and GHR transcripts were detected in isolated gastric glands, gastric cell fractions, and intestinal mucosa lineages. Human PRLR and GHR transcripts were also observed throughout the cancerous progression of the colonic and gastric mucosa from adenomas to colonic liver metastasis and gastrointestinal cancer cell lines at various stages of growth and differentiation. Prolactin (PRL) produced no detectable effect on M1 gastric mucin secretion in HT-29 cells adapted to methotrexate (HT-29-MTX) or on acid secretion in isolated rabbit parietal cells. GHRd3, an isoform of human GHR transcript missing exon 3, was also broadly expressed and was the only form found in gastric and colorectal adenocarcinomas. Interestingly, several extra bands of polymerase chain reaction products of the human PRLR, which were smaller than the expected size, were observed not only in the GI tract but also in liver and T-47D breast cancer cells. These products from human intestinal and breast cancer cell lines were subsequently subcloned and sequenced, and we isolated six isoforms of the receptor transcripts. One of these clones encodes a putative human PRL binding protein. The expression of PRL and PRLR transcripts was also clearly observed in intraepithelial lymphocytes purified from the mouse intestine. The widespread expression of the PRL and GH receptor transcripts in gastric and intestinal mucosal lineages, particularly in epithelia, suggests regulatory roles of these hormones on digestive and immune functions, including metabolism, growth, or differentiation.
Article
We have studied the transcriptional activation of the human TNF-alpha gene by the superantigen staphylococcal enterotoxin A (SEA) in the human premonocytic cell line THP-1. Nuclear proteins from SEA-stimulated THP-1 cells bound strongly to kappa 3, the most proximal of three putative NF-kappa B binding sites (kappa 1-kappa 3) found in the 5' regulatory region of the TNF-alpha gene, but only weakly to kappa 1, the most distal of the NF-kappa B binding sites, and showed no binding to kappa 2. The mobility of the kappa 3-nucleoprotein complex was identical to that of complexes formed between nuclear proteins and the consensus NF-kappa B seuqence. Moreover, both 5' and 3' mutants of kappa 3 were unable to displace kappa 3 binding, suggesting that the kappa 3 binding complex induced by SEA has the characteristics of NF-kappa B. Studies using Abs directed against the NF-kappa B subunits p50 and p65 suggested that both p50 and p65 bind to the kappa 3 sequence. Reporter gene assays showed that deletion of kappa 3 (-99 to -89 bp) and point mutation of the three 5' guanine bases in the kappa 3 sequence reduced the inducibility of the TNF-alpha promoter by SEA and LPS. These results indicate that superantigen induces NF-kappa B in human monocytic cells and suggest that binding of NF-kappa B to the kappa 3 site of the TNF-alpha promoter plays an important role in the transcriptional activation of the TNF-alpha gene by superantigen.
Article
Prolactin (PRL) is a potent mitogen in cultured astrocytes. Because one of the major effects of astrocyte proliferation is the expression of inflammatory cytokines, we examined the effect of PRL-induced mitogenesis on the expression of interleukin-1 (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-alpha (TGF-alpha) in cultured astrocytes. Astrocytes were stimulated with PRL or growth hormone (GH), and the expression of cytokines was determined by immunohistochemistry and Western blot analysis. Following incubation of astrocytes with 1 nM PRL for 6 h, strong positive staining of IL-1 alpha and TNF-alpha, but not TGF-alpha, was found. No detectable staining for the above cytokines was found in vehicle, or GH treated astrocytes. When astrocytes were incubated in the presence of 1 nM PRL for 18 h, strong positive staining for IL-1 alpha and TGF-alpha was found. Immunocytochemical analysis of the expression of TNF-alpha and IL-1 alpha in PRL stimulated astrocytes suggested that the expression of IL-1 alpha preceded the expression of TNF-alpha. To confirm this observation, Western blot analyses were performed on extracts from astrocytes incubated with 1 nM PRL in unstimulated astrocytes, IL-1 alpha levels were not detectable. In astrocytes stimulated with 1 nM PRL, expression of IL-1 alpha was clearly detected after 1 h of incubation, and IL-1 alpha levels continued to increase during the course of the experiment (6 h). In contrast, in astrocytes stimulated with 1 nM PRL, an increase in the expression of TNF-alpha was first apparent after 2 h of incubation.(ABSTRACT TRUNCATED AT 250 WORDS)
Article
Autoimmune responses are initiated by MHC class II-restricted T cell responses directed against tissue-specific autoantigens. Furthermore, HLA-DR expression in thyroid epithelial cells is a prominent feature of autoimmune thyroid disease. In the present work, we were particularly interested in a phenothiazine, a neuroleptic and anti-depressant drug of pharmacologic importance named alimemazine. Our interest in this compound stems from previous findings of immune effects of this and other phenothiazines. We demonstrate that MHC class II Ags can be experimentally induced on thyroid cells by pharmacologic concentrations of alimemazine, a drug commonly used in psychiatry. In contrast, MHC class II Ags were not induced on the lymphoid cell lines Raji and Jurkat. Expression of MHC class II Ag on the surface of the cloned human thyroid cell hybridoma, GEJ, was demonstrated by flow cytometry. Moreover, by using Northern blot and Southern blot analyses, this finding was confirmed at the molecular level in GEJ and in murine thyroid epithelial cell cultures, respectively. The functional role of phenothiazine-, de novo-induced MHC class II Ags on thyroid cells was assessed by both syngeneic murine thyroglobulin-specific and allogeneic proliferative T cell responses. These results suggest that antidepressant drugs of the phenothiazine type could play a role in the induction and the perpetuation of thyroid autoimmune disorders, through induction of class II restriction elements on normally class II-negative thyroid epithelial cells.
Article
Staphylococcal superantigens bind to MHC class II molecules and induce transcriptional activation of IL-1 beta and TNF-alpha genes in human monocytic cells. The understanding of the mechanisms by which superantigens activate cytokine gene expression is incomplete. In this study, we demonstrate that toxic shock syndrome toxin-1 (TSST-1) and staphylococcal enterotoxins A and B induce the activation of NF-kappa B, a transcriptional enhancer that binds to sequences found in both the IL-1 beta and TNF-alpha promoters. Electrophoretic mobility-shift assays showed a rapid induction of nuclear proteins that bound to the consensus kappa B motif. Furthermore, TSST-1 potently stimulated chloramphenicol acetyltransferase (CAT) expression by THP-1 cells transfected with a consensus NF-kappa B-promoter CAT construct, indicative of induction of NF-kappa B enhancer function. Induction of both NF-kappa B DNA-binding proteins and NF-kappa B enhancer function was down-regulated by inhibitors of protein kinase C and protein tyrosine kinase, indicating a role for these protein kinases in the induction of NF-kappa B by MHC class II ligands. Using neutralizing antibodies, we demonstrated that after the stimulation of cells with TSST-1, TNF-alpha, but not IL-1 beta, acted to up-regulate binding of NF-kappa B to DNA and the activation of the NF-kappa B-promoter CAT construct. These results indicate that induction of NF-kappa B by superantigens is up-regulated in part by an autocrine loop involving TNF-alpha.
Article
The immune response is regulated by locally released factors, collectively referred to as cytokines. Data on the human immune system have convincingly demonstrated that the hormone prolactin (PRL), in addition to exerting its endocrine control on the immune system, acts as a cytokine in that it is released within the immune system and regulates the lymphocyte response by paracrine and autocrine mechanisms. Both lymphocyte and pituitary PRLs are under the control of immune factors. Synthesis of human PRL by lymphocytes is induced by T-cell stimuli, while increased release of PRL by the pituitary, observed in vivo after immune challenge, may be mediated by cytokines produced by monocyte-macrophages. Since hyperprolactinemia and hypoprolactinemia are both immunosuppressive, physiological levels of circulating PRL must be necessary to maintain basal immunocompetence. The effects of Cyclosporin (CsA) on IL-2 and PRL gene activation and the analysis of the intracellular signaling events downstream IL-2 and PRL receptors suggest coordinate actions of these two cytokines during T cell activation.
Article
Since their discovery nearly ten years ago, T helper 1 (Th1) and Th2 subsets have been implicated in the regulation of many immune responses. In this article, Tim Mosmann and Subash Sad discuss the increasing number of T-cell subsets defined by cytokine patterns; the differentiation pathways of CD4+ and CD8+ T cells; the contribution of other cell types to these patterns; and the cytokine interactions during infection and pregnancy.
Article
By virtue of their functional antagonism, Th1 cells or cells producing the same cytokines as Th1 cells may behave as "suppressor cells' with respect to Th2 cells and vice versa. An excessive Th1- or Th2-like response may favor the development of different autoimmune diseases. As can be expected from their physiological role, Th-1 cytokines participate in autoimmune diseases with a preferential delayed type hypersensitivity component, i.e. in those diseases in which cytotoxic T cells attack organ-specific target cells. Autoimmune diseases with a predominant Th1 component include experimental autoimmune encephalitis and insulin-dependent diabetes mellitus. In contrast, Th2-type responses participate in systemic autoimmune diseases with a strong humoral component. Such diseases probably include certain drug-induced states of autoaggression, namely mercury-induced autoimmune disease and chlorpromazine-induced autoimmunity. It is tempting to speculate that therapeutic interventions designed to recover a normal Th1/Th2 balance will provide a useful etiological strategy for the re-establishment of self-tolerance.
Article
Interleukin-12 (IL-12) is a proinflammatory cytokine produced by antigen-presenting cells in response to many microbial infections. IL-12 plays an important role in the generation of T helper type-1 cells, which favor cell-mediated immune response. IL-12 is composed of two different subunits, p40 and p35, whose expression can be regulated concomitantly or differentially. Monocytic cells, the major producers of IL-12, can be primed by interferon-gamma (IFN-gamma) to produce optimal amounts of IL-12 in response to LPS stimulation as a consequence of bacterial infection. The priming effect is exerted primarily at the transcriptional level on the p40 promoter in conjunction with the effects of LPS, possibly by inducing specific transcription factors, which individually have no direct effect but which cooperatively can activate the promoter. We examined in detail one of these DNA-protein interactions observed around an Ets-2 element situated at -211/-207 of the p40 promoter, which is known to be a functionally critical site. This region interacts with a nuclear complex termed F1 that appears to be highly inducible by either IFN-gamma treatment for 16 h or lipopolysaccharide stimulation for 8 h. F1 binding to the Ets-2 site requires a considerable amount of spacing around the Ets-2 site, as revealed by gel mobility shift and in vitro methylation assays. Supershift experiments and DNA affinity purification indicated that both Ets-2 and a novel, antigenically related protein with an approximate molecular mass of 109 kDa are part of the F1 complex, together with additional components including IRF-1 and c-Rel. This novel protein is designated GLp109 for its inducibility by IFN-gamma or lipopolysaccharide. Its possible role in the activation of the IL-12 p40 promoter is discussed.
Article
It has been demonstrated that prolactin (PRL) is a potent immunomodulator that exerts stimulatory effects on physiological responses of immune cells. In the present research we have investigated whether PRL may influence nitric oxide (NO) and/or tumor necrosis factor-alpha (TNF-alpha) production in neutrophils obtained from inflammatory exudate of carrageenin-induced experimental pleurisy in the rat. In this acute model of inflammation the role of endogenous NO was evaluated using an inhibitor of NO-synthase, NG-nitro-L-arginine methyl ester (L-NAME). A treatment of animals with L-NAME (10 mg/kg s.c.) induced a reduction of volume and cell number of pleural exudate and a decrease of nitrite production (measured by the Griees reaction) by polymorphonuclear cells after 24 h of incubation, while D-NAME, the inactive isomer, was without effect. Neutrophils from ovine prolactin (oPRL) treated rats (5 mg/kg for 5 times s.c.) or from rats with a hyperprolactinaemia induced by pituitary gland graft produced higher amounts of NO both after 24 and 48 h of incubation. On the contrary, a clear reduction in the production of NO was found in neutrophils from rats treated with bromocriptine (BRC) (2 mg/kg s.c.), a dopamine D2-receptor agonist. TNF-alpha production (measured by MTT/cytotoxic assay) by neutrophils was markedly increased in PRL-treated or pituitary-grafted rats in comparison to controls, whereas BRC treatment reduced TNF-alpha production.