Brain Behavior and Immunity

Publications in this journal

• Article: Imatinib Methanesulfonate Reduces Hippocampal Amyloid-Beta and Restores Cognitive Function Following Repeated Endotoxin Exposure.

  Marielle K Weintraub, Courtney M Bisson, Jessica N Nouri, Benjamin T Vinson, Dinko Kranjac, Micah J Eimerbrink, Gary W Boehm, Michael J Chumley
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  ABSTRACT: Alzheimer's disease (AD) is characterized, in part, by atrophy of the adult brain and increased presence of extracellular amyloid-beta (Aβ) plaques. Previous studies in our lab have shown that peripheral inflammation can lead to increased central Aβ and deficits in learning and memory. In order to determine whether Aβ accumulation in the brain is responsible for the learning deficits, we attempted to decrease peripheral production of Aβ in order to reduce central Aβ accumulation. It has previously been shown that Aβ is produced in large quantities in the liver, and is transferred across the blood-brain barrier (BBB). Recent research has shown that peripheral treatment with imatinib methanesulfonate salt (IM), known to interfere with the interaction between gamma (γ)-secretase and the γ-secretase activating protein (GSAP), decreases the cleavage of peripheral amyloid precursor protein into Aβ. Because IM poorly penetrates the BBB, we hypothesized that co-administration of IM with LPS would decrease peripheral production of Aβ in the presence of LPS-induced inflammation, leading to a decrease in Aβ accumulation in the hippocampus. We show that peripheral IM treatment eliminates hippocampal Aβ elevation that follows LPS-induced peripheral inflammation. Importantly, IM also eliminates the cognitive impairment seen following 7 consecutive days of LPS administration, implicating Aβ peptides as a likely cause of these cognitive deficits.
  Brain Behavior and Immunity 05/2013;
• Article: Television viewing, C-reactive protein, and depressive symptoms in older adults.

  Mark Hamer, Lydia Poole, Nadine Messerli-Bürgy
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  ABSTRACT: There is emerging evidence for a link between sedentary behavior and mental health, although the mechanisms remain unknown. We tested if an underlying inflammatory process explains the association between sedentary behavior and depressive symptoms. We conducted a two year follow-up of 4,964 (aged 64.5 ± 8.9 yrs) men and women from the English Longitudinal Study of Ageing, a cohort of community dwelling older adults. Self-reported TV viewing time was assessed at baseline as a marker of leisure time sedentary behavior. The 8-item Centre of Epidemiological Studies Depression (CES-D) scale was administered to measure depressive symptoms at follow-up. At baseline, TV time was associated with C-reactive protein (CRP), adjusted geometric mean CRP values were 2.94mg/L, (<2hrs/d TV); 3.04 mg/L, (2 to 4 hrs/d TV); 3.29mg/L, (4 to 6 hrs/d TV); 3.23 mg/L, (>6 hrs/d TV). We observed both a direct association of TV time on CES-D score at follow-up (B =0.08, 95% CI, 0.05, 0.10) and indirect effects (B =0.07, 95% CI, 0.05, 0.08). The indirect effects were largely explained through lack of physical activity, smoking, and alcohol, but not by CRP or body mass index.
  Brain Behavior and Immunity 05/2013;
• Article: The influence of vitamin D supplementation on melatonin status in patients with multiple sclerosis.

  Daniel Golan, Elsebeth Staun-Ram, Lea Glass-Marmor, Idit Lavi, Rozenberg Orit, Sara Dishon, Mira Barak, Sophia Ish-Shalom, Ariel Miller
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  ABSTRACT: BACKGROUND: Multiple Sclerosis (MS) incidence is higher in geographic regions with less sunlight exposure. Both vitamin D and melatonin are essential mediators of the effect of sunlight in health, and as such are candidates to play a key role in MS. We hypothesized that vitamin D and melatonin may have related influences in patients with MS. METHODS: In a randomized, double blind study of 40 IFN-β treated MS patients, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 19 patients received 4,370 IU vitamin D3 per day (high dose) for one year. Serum 25-hydroxy-vitamin-D (25-OH-D) and night time urine melatonin metabolite, 6-sulphatoxy-melatonin (6-SMT), were measured at baseline, 3 months and 1 year from enrolment. RESULTS: After 3 months supplementation, 25-OH-D levels increased and night-time melatonin secretion decreased significantly in the high dose group, but not in the low dose group. After 1 year, a decrease in 25-OH-D levels, accompanied by an increase of urine nighttime 6-SMT were observed in the high dose group. Percent change in serum 25-OH-D was significantly and negatively correlated with percent change in urine 6-SMT after 3 months and between 3 months to 1 year. 25-OH-D levels by the end of the study were significantly and negatively correlated to BMI. CONCLUSIONS: Melatonin secretion is negatively correlated with alterations in serum 25-OH-D in IFN-β treated patients with MS. The finding suggests that melatonin should be considered as a potential mediator of vitamin D neuro-immunomodulatory effects in patients with MS.
  Brain Behavior and Immunity 05/2013;
• Article: Maternal immune stimulation during pregnancy shapes the immunological phenotype of offspring.

  Mili Mandal, Robert Donnelly, Stella Elkabes, Pan Zhang, Dan Davini, Brian T David, Nicholas M Ponzio
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  ABSTRACT: Epidemiological studies have associated infection during pregnancy with increased risk of neurodevelopmental disorders in children, which is modeled in rodents by stimulating the immune system of pregnant dams with microorganisms or their mimics, such as poly(I:C) or LPS. In two prenatal mouse models, we show that in utero exposure of the fetus to cytokines/inflammatory mediators elicited by maternal immune stimulation with poly(I:C) yields offspring that exhibit a proinflammatory phenotype due to alterations in developmental programming of their immune system. Changes in the innate and adaptive immune elements of these pro-inflammatory offspring result in more robust responses following exposure to immune stimuli than those observed in control offspring from PBS-injected pregnant dams. In the first model, offspring from poly(I:C)-injected immunologically naïve dams showed heightened cellular and cytokine responses 4 hrs after injection of zymosan, a TLR2 agonist. In the second model, using dams with immunological memory, poly(I:C) injection during pregnancy produced offspring that showed preferential differentiation toward Th17 cell development, and earlier onset of clinical symptoms of EAE following immunization with MOG35- 55. Such "fetal programming" in offspring from poly(I:C)-injected dams not only persists into neonatal and adult life, but also can have profound consequences on health and disease.
  Brain Behavior and Immunity 05/2013;
• Article: Dichotomy of CCL21 and CXCR3 in nerve injury-evoked and autoimmunity-evoked hyperalgesia.

  Katja Schmitz, Geethanjali Pickert, Nina Wijnvoord, Annett Häussler, Irmgard Tegeder
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  ABSTRACT: The chemokine CCL21 is released from injured neurons and acts as a ligand of the chemokine receptor, CXCR3, which likely contributes to pro-inflammatory adaptations and secondary neuronal damage. CCL21-CXCR3 signalling may therefore impact on the development of neuropathic pain. By using the respective knockout mice we show that deficiency of CCL19/21 in plt/plt mice attenuates nerve injury evoked pain but not the hyperalgesia evoked by autoimmune encephalomyelitis (EAE). Oppositely, CXCR3-deficiency had no protective effect after traumatic nerve injury but reduced EAE-evoked hyperalgesia and was associated with reduced clinical EAE scores, a reduction of the pro-inflammatory cell infiltration and reduced upregulation of interferon gamma and interleukin-17 in the spinal cord. In contrast, microglia activation in the spinal cord after traumatic sciatic nerve injury was neither attenuated in CXCR3(-/-) nor plt/plt mice, nor in double knockouts. However, the severity of EAE, but not the hyperalgesia, was also reduced in plt/plt mice, which was associated with reduced infiltration of the spinal cord with CCR7+ T-cells, an increase of CD25+ T-cells and reduced upregulation of CXCL9 and 10, CCL11 and 12. The data show that CCL21 and CXCR3 have dichotomous functions in traumatic and EAE-evoked neuropathic pain suggesting diverse mechanisms likely requiring diverse treatments although both types of neuropathic pain are mediated in part through the immune activation.
  Brain Behavior and Immunity 04/2013;
• Article: Malaise, Melancholia and Madness: The Evolutionary Legacy of an Inflammatory Bias.

  Charles L Raison, Andrew H Miller
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  ABSTRACT: Evolutionary imperatives bred a vigorous and highly orchestrated behavioral and immune response to the microbial world that served to promote species survival and propagation. The resultant legacy is an inflammatory bias which goes largely unchecked in the modern world and is provoked not only by pathogens but also now by people. In this commentary, the authors' contributions to the Special Issue on Inflammation and Mental Health are described, beginning with the origins of the inflammatory bias, its roots in genetic predispositions to behavioral adaptations and ultimately maladaptations, and its consequences on the developing brain. In addition, the mechanisms by which the immune system engages behavior are described including a central role for the inflammasome which may serve to link psychological stress with inflammatory and behavioral responses. Neurotransmitter systems that mediate effects of the immune system on behavior are also described along with interactions of the inflammatory bias with depression and their convergent impact on the response to stress and medical illness. Finally, translational implications are discussed including data from a clinical trial using a cytokine antagonist in depressed patients, which suggests an interaction of the inflammatory bias with other evolutionary legacies including those related to food consumption and their modern consequences of obesity and the metabolic syndrome. Taken together, the articles offer a sampling of the rich literature that has evolved regarding the role of the immune system in behavioral disorders. The grounding of this relationship in our evolutionary past may serve to inform future research both theoretically and therapeutically.
  Brain Behavior and Immunity 04/2013;
• Article: Transcriptional Signatures Related to Glucose and Lipid Metabolism Predict Treatment Response to the Tumor Necrosis Factor Antagonist Infliximab in Patients with Treatment-Resistant Depression.

  Divya Mehta, Charles L Raison, Bobbi J Woolwine, Ebrahim Haroon, Elisabeth B Binder, Andrew H Miller, Jennifer C Felger
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  ABSTRACT: The tumor necrosis factor (TNF) antagonist infliximab was recently found to reduce depressive symptoms in patients with increased baseline inflammation as reflected by a plasma C-reactive protein concentration >5mg/L. To further explore predictors and targets of response to infliximab, differential gene expression was examined in peripheral blood mononuclear cells from infliximab responders (n=13) versus non-responders (n=14) compared to placebo at baseline and 6hr, 24hr, and 2 weeks after the first infliximab infusion. Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. One-hundred-forty-eight gene transcripts were significantly associated (1.2 fold, adjusted p⩽0.01) with response to infliximab and were distinct from placebo responders. Transcripts predictive of infliximab response were associated with gluconeogenesis and cholesterol transport, and were enriched in a network regulated by hepatocyte nuclear factor (HNF)4-alpha, a transcription factor involved in gluconeogenesis and cholesterol and lipid homeostasis. Of the 148 transcripts differentially expressed at baseline, 48% were significantly regulated over time in infliximab responders, including genes related to gluconeogenesis and the HNF4-alpha network, indicating that these predictive genes were responsive to infliximab. Responders also demonstrated inhibition of genes related to apoptosis through TNF signaling at 6hr and 24hr after infusion. Transcripts down-regulated in responders 2 weeks after infliximab were related to innate immune signaling and nuclear factor-kappa B. Thus, baseline transcriptional signatures reflective of alterations in glucose and lipid metabolism predicted antidepressant response to infliximab, and infliximab response involved regulation of metabolic genes and inhibition of genes related to innate immune activation.
  Brain Behavior and Immunity 04/2013;
• Article: Toll-like receptor 9 deficiency impacts sensory and motor behaviors.

  Veronika Khariv, Kevin Pang, Richard J Servatius, Brian T David, Matthew Goodus, Kevin D Beck, Robert F Heary, Stella Elkabes
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  ABSTRACT: Toll-like receptors (TLRs) mediate the induction of the innate immune system in response to pathogens, injury and disease. However, they also play non-immune roles and are expressed in the central nervous system (CNS) during prenatal and postnatal stages including adulthood. Little is known about their roles in the CNS in the absence of pathology. Several members of the TLR family have been implicated in the development of neural and cognitive function although the contribution of TLR9 to these processes has not been well defined. The current studies were undertaken to determine whether developmental TLR9 deficiency affects motor, sensory or cognitive functions. We report that TLR9 deficient (TLR9(-/-)) mice show a hyper-responsive sensory and motor phenotype compared to wild type (TLR9(+/+)) controls. This is indicated by hypersensitivity to thermal stimuli in the hot plate paw withdrawal test, enhanced motor-responsivity under anxious conditions in the open field test and greater sensorimotor reactivity in the acoustic startle response. Prepulse inhibition (PPI) of the acoustic startle response was also enhanced, which indicates abnormal sensorimotor gating. In addition, subtle, but significant, gait abnormalities were noted in the TLR9(-/-) mice on the horizontal balance beam test with higher foot slip numbers than TLR9(+/+) controls. In contrast, spatial learning and memory, assessed by the Morris water maze, was similar in the TLR9(-/-) and TLR9(+/+) mice. These findings support the notion that TLR9 is important for the appropriate development of sensory and motor behaviors.
  Brain Behavior and Immunity 04/2013;
• Article: Inflammatory activation and cholinergic anti-inflammatory system in eating disorders.

  Karina S Macdowell, Marina Díaz-Marsá, Itziar Güemes, Alberto Rodríguez, Juan Carlos Leza, José Luis Carrasco
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  ABSTRACT: Dysfunctional serotoninergic regulation and hypothalamic-pituitary-adrenal (HPA) axis overreactivity have been consistently reported in research studies with eating disorders (ED). In addition, the links between stress response, serotonin function, HPA axis and inflammatory mechanisms in ED have also been suggested in a number of studies. In our study, inflammatory parameters in white blood cells were investigated in 26 female patients with ED and 25 healthy control subjects matched for sex, age and ethnicity. Patients were free of medication for at least two weeks at the time of the study. Results showed a significant increase in plasma levels of the proinflammatory cytokine IL1β and the protein expression of cyclooxygenase 2 (COX2) in peripheral mononuclear blood cells (PMBC) in ED patients compared with controls. As well as a significant increase of the oxidative-nitrosative marker TBARS (Thiobarbituric Acid Reactive Substances) in plasma. These findings were associated with increased expression of the alpha7 subunit of the nicotinic receptor (α7nAChR) in PMBC in ED patients independent of plasma cotinine levels. These results suggest that a pro-inflammatory and oxidant phenotype might be present in ED patients. Further research on cellular inflammatory and anti-inflammatory pathways might be oriented to investigate differences between ED subtypes and to search for new potential targets for pharmacological treatment.
  Brain Behavior and Immunity 04/2013;
• Article: Loving-Kindness Meditation Practice Associated with Longer Telomeres in Women.

  Elizabeth A Hoge Md, Maxine M Chen Bs, Esther Orr Bs, Christina A Metcalf Ba, Laura E Fischer Ba, Mark H Pollack Md, Immaculata Devivo, Naomi M Simon Md
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  ABSTRACT: Relatively short telomere length may serve as a marker of accelerated aging, and shorter telomeres have been linked to chronic stress. Specific lifestyle behaviors that can mitigate the effects of stress might be associated with longer telomere lengths. Previous research suggests a link between behaviors that focus on the well-being of others, such as volunteering and caregiving, and overall health and longevity. We examined relative telomere length in a group of individuals experienced in Loving-Kindness Meditation (LKM), a practice derived from the Buddhist tradition which utilizes a focus on unselfish kindness and warmth towards all people, and control participants who had done no meditation. Blood was collected by venipuncture, and Genomic DNA was extracted from peripheral blood leukocytes. Quantitative real time PCR was used to measure relative telomere length (RTL) (Cawthon, 2002) in fifteen LKM practitioners and 22 control participants. There were no significant differences in age, gender, race, education, or exposure to trauma, but the control group had a higher mean body mass index (BMI) and lower rates of past depression. The LKM practitioners had longer RTL than controls at the trend level (p=.083); among women, the LKM practitioners had significantly longer RTL than controls, (p=.007), which remained significant even after controlling for BMI and past depression. Although limited by small sample size, these results offer the intriguing possibility that LKM practice, especially in women, might alter RTL, a biomarker associated with longevity.
  Brain Behavior and Immunity 04/2013;
• Article: Tryptophan Metabolism and Immunogenetics in Major Depression: A role for interferon-γ gene.

  Aye Mu Myint, Brigitta Bondy, Thomas C Baghai, Daniela Eser, Caroline Nothdurfter, Cornelius Schüle, Peter Zill, Norbert Müller, Rainer Rupprecht, Markus J Schwarz
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  ABSTRACT: The tryptophan metabolism and immune activation play a role in pathophysiology of major depressive disorders. The pro-inflammatory cytokine interferon-γ transcriptionally induces the indoleamine 2,3-dioxygenase enzyme that degrades the tryptophan and thus induces serotonin depletion. The polymorphism of certain cytokine genes was reported to be associated with major depression. We investigated the association between interferon-γ (IFNγ) gene CA repeat polymorphism, the profile of serotonin and tryptophan pathway metabolites and clinical parameters in 125 depressed patients and 93 healthy controls. Compared to controls, serum tryptophan and 5-hydroxyindoleacetic acid (5HIAA) concentrations in the patients were significantly lower and serum kynurenine concentrations were significantly higher at baseline (p<0.0001). The presence of IFNγ CA repeat allele 2 homozygous has significant association with higher kynurenine concentrations in controls (F=4.47, p=0.038) as well as in patients (F=3.79, p=0.045). The existence of interferon-γ CA repeat allele 2 (homo- or heterozygous) showed significant association with increase of tryptophan breakdown over time during the study period (F=6.0, p=0.019). The results indicated the association between IFNγ CA repeat allele 2, tryptophan metabolism and the effect of medication.
  Brain Behavior and Immunity 04/2013;
• Article: Lower CSF Interleukin-6 predicts future depression in a population-based sample of older women followed for 17 years.

  Silke Kern, Ingmar Skoog, Anne Börjesson-Hanson, Kaj Blennow, Henrik Zetterberg, Svante Ostling, Jürgen Kern, Pia Gudmundsson, Thomas Marlow, Lars Rosengren, Margda Waern
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  ABSTRACT: Objective The literature regarding cerebrospinal fluid (CSF) cytokines in geriatric depression is sparse. The aim of this study was to examine associations between CSF interleukin-6 (IL-6) and related proinflammatory cytokines and current and future depression in a population-based sample of older women who were followed for 17 years. Methods 83 non-demented women aged 70-84 years who participated in the Prospective Population Study of Women in Gothenburg, Sweden took part in a lumber puncture in 1992-3. CSF- IL-6, interleukin-1β (IL-1β), interleukin- 8 (IL-8) and tumor necrosis factor-α (TNF-α) were measured. Psychiatric symptoms were rated with the Comprehensive Psychopathological Rating Scale at baseline and at three subsequent face-to-face examinations. Depression (major or minor) was diagnosed in accordance with DSM-IV/DSM-IV research criteria. Results At baseline, women with ongoing depression had lower levels of IL-6 (p< 0.04), IL-8 (p<0.05) and TNF-α (p<0.05) compared with those without depression. In women without depression at baseline, lower CSF IL-6 levels predicted depression at one or more follow-up examination (p<0.03). Results from the generalized linear mixed logistic model using all baseline and follow-up data on depression status and Mini Mental State Examination score showed a significant relationship between IL-6 and depression (p= 0.005 OR 0.370 CI[0.184-0.744]). Conclusion Lower levels of CSF IL-6 were associated with current depression and with future depression during a follow-up of almost two decades. Our findings suggest that lower levels of CSF IL-6 may be related to depression vulnerability in later life.
  Brain Behavior and Immunity 04/2013;
• Article: Menstrual cycle and reproductive aging alters immune reactivity, NGF expression, antioxidant enzyme activities, and intracellular signaling pathways in the peripheral blood mononuclear cells of healthy women.

  Hannah P Priyanka, Utsav Sharma, Srinivasan Gopinath, Varun Sharma, Lalgi Hima, Srinivasan Thyagarajan
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  ABSTRACT: Reproductive senescence in women is a process that begins with regular menstrual cycles and culminates in menopause followed by gradual development of diseases such as autoimmune diseases, osteoporosis, neurodegenerative diseases, and hormone-dependent cancers. The age-associated impairment in the functions of neuroendocrine system and immune system results in menopause which contributes to subsequent development of diseases and cancer. The aim of this study is to characterize the alterations in immune responses, compensatory factors such as nerve growth factor (NGF) and antioxidant enzyme activities, and the molecular mechanisms of actions in the peripheral blood mononuclear cells (PBMCs) of young (follicular and luteal phases), middle-aged, and old healthy women. Peripheral blood mononuclear cells were isolated from young women in follicular and luteal phases of the menstrual cycle (n=20; 22.6±2.9 yrs.), middle-aged women (n=19; 47.1±3.8 yrs.; perimenopausal) and old (n=16; 63.2± 4.7 yrs.; postmenopausal) women and analyzed for Concanavalin (Con A)-induced proliferation of lymphocytes and cytokine (IL-2 and IFN-γ) production, expression of NGF, p-NF-κB, p-ERK, p-CREB, and p-Akt, antioxidant enzymes [superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx), glutathione-S-transferase (GST)], extent of lipid peroxidation, and nitric oxide (NO) production. Serum gonadal hormones (17β-estradiol and progesterone) were also measured. A characteristic age- and menstrual cycle-related change was observed in the serum gonadal hormone secretion (estrogen and progesterone), T lymphocyte proliferation and IFN-γ production. Salient features include the age-related decline observed in target-derived growth factors (lymphocyte NGF expression), signaling molecules (p-ERK/ERK and p-CREB/CREB ratios) and compensatory factors such as the activities of plasma and PBMC antioxidant enzymes (SOD and catalase) and NO production. Further, an age-associated increase in p-NF-kB expression and lipid peroxidation was observed. Also, serum 17β-estradiol levels were positively correlated with IFN-γ production, SOD activity and NGF expression in the PBMCs. These results suggest that alterations in the levels of gonadal hormones are associated with immunosenescence characterized by decreased IFN-γ production and proliferation of T lymphocytes, decline in NGF expression, SOD and catalase activities, NO production, and signaling mechanisms and thus, may increase the incidence of diseases and cancer in women.
  Brain Behavior and Immunity 03/2013;
• Article: Depression inhibits the anti-inflammatory effects of leisure time physical activity and light to moderate alcohol consumption.

  Edward C Suarez, Nicole L Schramm-Sapyta, Tracey Vann Hawkins, Alaattin Erkanli
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  ABSTRACT: Light to moderate alcohol consumption and leisure time physical activity (LTPA) are independently associated with lower levels of high sensitivity C-reactive protein (CRP), a predictor of cardiometabolic risk. In contrast, depression, ranging from low mood disturbance to major depressive disorder, has been associated with elevated CRP. To test the hypothesis that depression attenuates the anti-inflammatory effects of LTPA and alcohol consumption, the current study tested the moderating effect of severity of depressive symptomatology on the relation of alcohol consumption and LTPA to CRP in 222 healthy adult men and women (18-65 years of age). Given the known effects of gender on inflammation, we also examined the effects of gender on the tested interactions. Depression was assessed using the Beck Depression Inventory. Frequency of alcohol consumption, hours of LTPA per week and other coronary risk/protective factors were assessed via self-report and structured interview. Fasting blood samples were used to measure CRP and lipids. As predicted, the interaction between LTPA and depressive symptomatology was significant (F = 5.29, p < .03) such that lower CRP was associated with the combination of decreased depressive symptomatology and increased LTPA. Among those with increased depressive symptoms, increased LTPA was not associated with higher CRP. Similarly, depression interacted with alcohol consumption in predicting CRP in men but not women (F = 5.03, p < .008) such that for men light to moderate alcohol consumption was associated with lower CRP but only among those with decreased depressive symptoms. Light to moderate alcohol consumption was not associated with lower CRP in those with increased depressive symptom severity. The pattern of the interactions between anti-inflammatory activities such as light to moderate alcohol consumption and LTPA and psychological distress as indexed by severity of depressive symptomatology suggests an important new avenue for future research.
  Brain Behavior and Immunity 03/2013;
• Article: Nerve-derived Transmitters Including Peptides Influence Cutaneous Immunology.

  Elizabeth N Madva, Richard D Granstein
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  ABSTRACT: Clinical observations suggest that the nervous and immune systems are closely related. For example, inflammatory skin disorders; such as psoriasis, atopic dermatitis, rosacea and acne; are widely believed to be exacerbated by stress. A growing body of research now suggests that neuropeptides and neurotransmitters serve as a link between these two systems. Neuropeptides and neurotransmitters are released by nerves innervating the skin to influence important actors of the immune system, such as Langerhans cells and mast cells, which are located within close anatomic proximity. Catecholamines and other sympathetic transmitters that are released in response to activation of the sympathetic nervous system are also able to reach the skin and affect immune cells. Neuropeptides appear to direct the outcome of Langerhans cell antigen presentation with regard to the subtypes of Th cells generated and neuropeptides induce the degranulation of mast cells, among other effects. Additionally, endothelial cells, which release many inflammatory mediators and express cell surface molecules that allow leukocytes to exit the bloodstream, appear to be regulated by certain neuropeptides and transmitters. This review focuses on the evidence that products of nerves have important regulatory activities on antigen presentation, mast cell function and endothelial cell biology. These activities are highly likely to have clinical and therapeutic relevance.
  Brain Behavior and Immunity 03/2013;
• Article: Characterization of the secretome of human tooth germ stem cells (hTGSCs) reveals neuro-protection by fine-tuning micro-environment.

  Mehmet Emir Yalvaç, Aysen Yarat, Dilek Mercan, Albert A Rizvanov, András Palotás, Fikrettin Sahin
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  ABSTRACT: Bone-marrow-derived mesenchymal stem cells (MSCs) demonstrate neuro-protective effects in several disease models. By producing growth-factors, cytokines and chemokines, they promote survival of neurons in damaged brain areas. Alternative MSC sources, such as human tooth germ stem cells (hTGSCs), have been investigated for their neuro-protective properties. They ameliorate effects of neuro-toxic agents by paracrine mechanisms, however these secreted bio-active molecules are not yet characterized. Therefore, the current study aimed to provide a detailed analysis of the secretome of hTGSCs. Brain cells were exposed to various toxic materials, including Alzheimer's β-amyloid peptide (βAP) and 6-hydroxy-dopamine (6-OHDA). When co-cultured with hTGSCs, the activity of a number of anti-oxidant enzymes (catalase, glutathione-s-transferase, glutathione-peroxidase, superoxide-dismutase) was increased and neuronal death/apoptosis was subsequently reduced. The composition of the secreted bio-active materials is influenced by various pre-existing factors such as oxygen deprivation and the age of cells (passage number). This report reveals for the first time that the neuro-protective secretome of hTGSCs and the micro-environment of cells have a mutual and dynamic impact on one another.
  Brain Behavior and Immunity 03/2013;
• Article: Negative regulation of TLX by IL-1β correlates with an inhibition of adult hippocampal neural precursor cell proliferation.

  Sinead M Ryan, Gerard W O'Keeffe, Caitriona O'Connor, Karen Keeshan, Yvonne M Nolan
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  ABSTRACT: Adult hippocampal neurogenesis is modulated by a number of intrinsic and extrinsic factors including local signalling molecules, exercise, aging and inflammation. Inflammation is also a major contributor to several hippocampal-associated disorders. Interleukin-1beta (IL-1β) is the most predominant pro-inflammatory cytokine in the brain, and an increase in its concentration is known to decrease the proliferation of both embryonic and adult hippocampal neural precursor cells (NPCs). Recent research has focused on the role of nuclear receptors as intrinsic regulators of neurogenesis, and it is now established that the orphan nuclear receptor TLX is crucial in maintaining the NPC pool in neurogenic brain regions. To better understand the involvement of TLX in IL-1β-mediated effects on hippocampal NPC proliferation, we examined hippocampal NPC proliferation and TLX expression in response to IL-1β treatment in an adult rat hippocampal neurosphere culture system. We demonstrate that IL-1β reduced the proliferation of hippocampal NPCs and TLX expression in a dose and time-dependent manner and that co-treatment with IL-1β receptor antagonist or IL-1 receptor siRNA prevented these effects. We also report a dose-dependent effect of IL-1β on the composition of cell phenotypes in the culture and on expression of TLX in these cells. This study thus provides evidence of an involvement of TLX in IL-1β-induced changes in adult hippocampal neurogenesis, and offers mechanistic insight into disorders in which neuroinflammation and alterations in neurogenesis are characteristic features.
  Brain Behavior and Immunity 03/2013;