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Yun-Hee Youm,
Thirumala-Devi Kanneganti,
Bolormaa Vandanmagsar,
Xuewei Zhu,
Anthony Ravussin,
Ayinuer Adijiang,
John S Owen,
Michael J Thomas,
Joseph Francis,
John S Parks, Vishwa Deep Dixit
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ABSTRACT: The collapse of thymic stromal cell microenvironment with age and resultant inability of the thymus to produce naive T cells contributes to lower immune-surveillance in the elderly. Here we show that age-related increase in 'lipotoxic danger signals' such as free cholesterol (FC) and ceramides, leads to thymic caspase-1 activation via the Nlrp3 inflammasome. Elimination of Nlrp3 and Asc, a critical adaptor required for inflammasome assembly, reduces age-related thymic atrophy and results in an increase in cortical thymic epithelial cells, T cell progenitors and maintenance of T cell repertoire diversity. Using a mouse model of irradiation and hematopoietic stem cell transplantation (HSCT), we show that deletion of the Nlrp3 inflammasome accelerates T cell reconstitution and immune recovery in middle-aged animals. Collectively, these data demonstrate that lowering inflammasome-dependent caspase-1 activation increases thymic lymphopoiesis and suggest that Nlrp3 inflammasome inhibitors may aid the re-establishment of a diverse T cell repertoire in middle-aged or elderly patients undergoing HSCT.
Cell reports. 01/2012; 1(1):56-68.
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ABSTRACT: [D-Lys3]-Growth Hormone Releasing Peptide-6 (DLS) is widely utilized in vivo and in vitro as a selective ghrelin receptor (GHS-R) antagonist. This antagonist is one of the most common antagonists utilized in vivo to block GHS-R function and activity. Here, we found that DLS also has the ability to modestly block chemokine function and ligand binding to the chemokine receptor CCR5. The DLS effects on RANTES binding and Erk signaling as well as calcium mobilization appears to be much stronger than its effects on MIP-1α and MIP-1β. CCR5 have been shown to act as major co-receptor for HIV-1 entry into the CD4 positive host cells. To this end, we also found that DLS blocks M-tropic HIV-1 propagation in activated human PBMCs. These data demonstrate that DLS may not be a highly selective GHS-R1a inhibitor and may also effects on other G-protein coupled receptor (GPCR) family members. Moreover, DLS may have some potential clinical applications in blocking HIV infectivity and CCR5-mediated migration and function in various inflammatory disease states.
International journal of medical sciences 01/2012; 9(1):51-8. · 2.24 Impact Factor
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ABSTRACT: [D-Lys3]-Growth Hormone Releasing Peptide-6 (DLS) is widely utilized in vivo and in vitro as a selective ghrelin receptor (GHS-R) antagonist. Unexpectedly, we identified that DLS also has the ability to block CXCL12 binding and activity through CXCR4 on T cells and peripheral blood mononuclear cells (PBMCs). Moreover, as CXCR4 has been shown to act as a major co-receptor for HIV-1 entry into CD4 positive host cells, we have also found that DLS partially blocks CXCR4-mediated HIV-1 entry and propagation in activated human PBMCs. These data demonstrate that DLS is not the specific and selective antagonist as thought for GHS-R1a and appears to have additional effects on the CXCR4 chemokine receptor. Our findings also suggest that structural analogues that mimic DLS binding properties may also have properties of blocking HIV infectivity, CXCR4 dependent cancer cell migration and attenuating chemokine-mediated immune cell trafficking in inflammatory disorders.
International journal of biological sciences 01/2012; 8(1):108-17. · 2.70 Impact Factor
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ABSTRACT: Clinical evidence that the blockade of IL-1β in type-2 diabetic patients improves glycemia is indicative of an autoinflammatory mechanism that may trigger adiposity-driven pancreatic damage. IL-1β is a key contributor to the obesity-induced inflammation and subsequent insulin resistance, pancreatic β-cell dysfunction, and the onset of type 2 diabetes. Our previous studies demonstrated that the ceramides activate the Nod-like receptor family, pyrin domain containing 3 (Nlrp3) inflammasome to cause the generation of mature IL-1β and ablation of the Nlrp3 inflammasome in diet-induced obesity improves insulin signaling. However, it remains unclear whether the posttranslational processing of active IL-1β in pancreas is regulated by the NLRP3 inflammasome or whether the alternate mechanisms play a dominant role in chronic obesity-induced pancreatic β-cell exhaustion. Here we show that loss of ASC, a critical adaptor required for the assembly of the NLRP3 and absent in melanoma 2 inflammasome substantially improves the insulin action. Surprisingly, despite lower insulin resistance in the chronically obese NLRP3 and ASC knockout mice, the insulin levels were substantially higher when the inflammasome pathway was eliminated. The obesity-induced increase in maturation of pancreatic IL-1β and pancreatic islet fibrosis was dependent on the NLRP3 inflammasome activation. Furthermore, elimination of NLRP3 inflammasome protected the pancreatic β-cells from cell death caused by long-term high-fat feeding during obesity with significant increase in the size of the islets of Langerhans. Collectively, this study provides direct in vivo evidence that activation of the NLRP3 inflammasome in diet-induced obesity is a critical trigger in causing pancreatic damage and is an important mechanism of progression toward type 2 diabetes.
Endocrinology 08/2011; 152(11):4039-45. · 4.46 Impact Factor
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ABSTRACT: Intermittent fasting (IF) improves healthy lifespan in animals by a mechanism involving reduced oxidative damage and increased resistance to stress. However, no studies have evaluated the impact of controlled meal frequency on immune responses in human subjects.
A study was conducted to establish the effects of controlled diets with different meal frequencies, but similar daily energy intakes, on cytokine production in healthy male and female subjects.
In a crossover study design with an intervening washout period, healthy normal weight middle-age male and female subjects (n = 15) were maintained for 2 months on controlled on-site one meal per day (OMD) or three meals per day (TMD) isocaloric diets. Serum samples and peripheral blood mononuclear cells (PBMCs) culture supernatants from subjects were analyzed for the presence of inflammatory markers using a multiplex assay.
There were no significant differences in the inflammatory markers in the serum of subjects on the OMD or TMD diets. There was an increase in the capacity of PBMCs to produce cytokines in subjects during the first month on the OMD or TMD diets.Lower levels of TNF-α, IL-17, MCP-1 and MIP-1β were produced by PBMCs from subjects on the OMD versus TMD diet.
PBMCs of subjects on controlled diets exhibit hypersensitivities to cellular stimulation suggesting that stress associated with altered eating behavior might affect cytokine production by immune cells upon stimulation. Moreover, stimulated PBMCs derived from healthy individuals on a reduced meal frequency diet respond with a reduced capability to produce cytokines.
Journal of Inflammation 03/2011; 8:6. · 2.26 Impact Factor
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ABSTRACT: The emergence of chronic inflammation during obesity in the absence of overt infection or well-defined autoimmune processes is a puzzling phenomenon. The Nod-like receptor (NLR) family of innate immune cell sensors, such as the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (Nlrp3, but also known as Nalp3 or cryopyrin) inflammasome are implicated in recognizing certain nonmicrobial originated 'danger signals' leading to caspase-1 activation and subsequent interleukin-1β (IL-1β) and IL-18 secretion. We show that calorie restriction and exercise-mediated weight loss in obese individuals with type 2 diabetes is associated with a reduction in adipose tissue expression of Nlrp3 as well as with decreased inflammation and improved insulin sensitivity. We further found that the Nlrp3 inflammasome senses lipotoxicity-associated increases in intracellular ceramide to induce caspase-1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevents obesity-induced inflammasome activation in fat depots and liver as well as enhances insulin signaling. Furthermore, elimination of Nlrp3 in obese mice reduces IL-18 and adipose tissue interferon-γ (IFN-γ) expression, increases naive T cell numbers and reduces effector T cell numbers in adipose tissue. Collectively, these data establish that the Nlrp3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.
Nature medicine 02/2011; 17(2):179-88. · 27.14 Impact Factor
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ABSTRACT: Emerging evidence suggests that increases in activated T cell populations in adipose tissue may contribute toward obesity-associated metabolic syndrome. The present study investigates three unanswered questions: 1) Do adipose-resident T cells (ARTs) from lean and obese mice have altered cytokine production in response to TCR ligation?; 2) Do the extralymphoid ARTs possess a unique TCR repertoire compared with lymphoid-resident T cells and whether obesity alters the TCR diversity in specific adipose depots?; and 3) Does short-term elimination of T cells in epididymal fat pad without disturbing the systemic T cell homeostasis regulate inflammation and insulin-action during obesity? We found that obesity reduced the frequency of naive ART cells in s.c. fat and increased the effector-memory populations in visceral fat. The ARTs from diet-induced obese (DIO) mice had a higher frequency of IFN-gamma(+), granzyme B(+) cells, and upon TCR ligation, the ARTs from DIO mice produced increased levels of proinflammatory mediators. Importantly, compared with splenic T cells, ARTs exhibited markedly restricted TCR diversity, which was further compromised by obesity. Acute depletion of T cells from epididymal fat pads improved insulin action in young DIO mice but did not reverse obesity-associated feed forward cascade of chronic systemic inflammation and insulin resistance in middle-aged DIO mice. Collectively, these data establish that ARTs have a restricted TCR-Vbeta repertoire, and T cells contribute toward the complex proinflammatory microenvironment of adipose tissue in obesity. Development of future long-term T cell depletion protocols specific to visceral fat may represent an additional strategy to manage obesity-associated comorbidities.
The Journal of Immunology 08/2010; 185(3):1836-45. · 5.79 Impact Factor
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Vishwa Deep Dixit
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ABSTRACT: With advancing age, the thymus undergoes striking fibrotic and fatty changes that culminate in its transformation into adipose tissue. As the thymus involutes, reduction in thymocytes and thymic epithelial cells precede the emergence of mature lipid-laden adipocytes. Dogma dictates that adipocytes are 'passive' cells that occupy non-epithelial thymic space or 'infiltrate' the non-cellular thymic niches. The provenance and purpose of ectopic thymic adipocytes during aging in an organ that is required for establishment and maintenance of T cell repertoire remains an unsolved puzzle. Nonetheless, tantalizing clues about elaborate reciprocal relationship between thymic fatness and thymopoietic fitness are emerging. Blocking or bypassing the route toward thymic adiposity may complement the approaches to rejuvenate thymopoiesis and immunity in elderly.
Current opinion in immunology 08/2010; 22(4):521-8. · 10.88 Impact Factor
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ABSTRACT: Age-related thymic involution is characterized by reduction in T cell production together with ectopic adipocyte development within the hematopoietic and thymic niches. Peroxisome proliferator-activated receptor gamma (PPARgamma) is required for adipocyte development, glucose homeostasis and is a target for several insulin-sensitizing drugs. Our prior studies showed that age-related elevation of PPARgamma expression in thymic stromal cells is associated with thymic involution. Here, using clinically relevant pharmacological and genetic manipulations in mouse models, we provide evidence that activation of PPARgamma leads to reduction in thymopoiesis. Treatment of aged mice with antihyperglycemic PPARgamma-ligand class of thiazolidinedione drug, rosiglitazone caused robust thymic expression of classical pro-adipogenic transcripts. Rosiglitazone reduced thymic cellularity, lowered the naïve T cell number and T cell receptor excision circles (TRECs) indicative of compromised thymopoiesis. To directly investigate whether PPARgamma activation induces thymic involution, we created transgenic mice with constitutive-active PPARgamma (CA-PPARg) fusion protein in cells of adipogenic lineage. Importantly, CA-PPARgamma transgene was expressed in thymus and in fibroblast-specific protein-1/S100A4 (FSP1(+)) cells, a marker of secondary mesenchymal cells. The CAPPARgamma fusion protein mimicked the liganded PPARgamma receptor and the transgenic mice displayed increased ectopic thymic adipogenesis and reduced thymopoiesis. Furthermore, the reduction in thymopoiesis in CA-PPARgamma mice was associated with higher bone marrow adiposity and lower hematopoietic stem cell progenitor pool. Consistent with lower thymic output, CAPPARgamma transgenic mice had restricted T cell receptor repertoire diversity. Collectively, our data suggest that activation of PPARgamma accelerates thymic aging and thymus-specific PPARgamma antagonist may forestall age-related decline in T cell diversity.
Aging cell 04/2010; 9(4):478-89. · 7.55 Impact Factor
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ABSTRACT: As the expanding obese population grows older, their successful immunologic aging will be critical to enhancing the health span. Obesity increases risk of infections and cancer, suggesting adverse effects on immune surveillance. Here, we report that obesity compromises the mechanisms regulating T-cell generation by inducing premature thymic involution. Diet-induced obesity reduced thymocyte counts and significantly increased apoptosis of developing T-cell populations. Obesity accelerated the age-related reduction of T-cell receptor (TCR) excision circle bearing peripheral lymphocytes, an index of recently generated T cells from thymus. Consistent with reduced thymopoiesis, dietary obesity led to reduction in peripheral naive T cells with increased frequency of effector-memory cells. Defects in thymopoiesis in obese mice were related with decrease in the lymphoid-primed multipotent progenitor (Lin-Sca1+Kit+ Flt3+) as well as common lymphoid progenitor (Lin-Sca1+CD117(lo)CD127+) pools. The TCR spectratyping analysis showed that obesity compromised V-beta TCR repertoire diversity. Furthermore, the obesity induced by melanocortin 4 receptor deficiency also constricted the T-cell repertoire diversity, recapitulating the thymic defects observed with diet-induced obesity. In middle-aged humans, progressive adiposity with or without type 2 diabetes also compromised thymic output. Collectively, these findings establish that obesity constricts T-cell diversity by accelerating age-related thymic involution.
Blood 09/2009; 114(18):3803-12. · 9.90 Impact Factor
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ABSTRACT: Aging of thymus is characterized by reduction in naive T cell output together with progressive replacement of lymphostromal thymic zones with adipocytes. Determining how calorie restriction (CR), a prolongevity metabolic intervention, regulates thymic aging may allow identification of relevant mechanisms to prevent immunosenescence. Using a mouse model of chronic CR, we found that a reduction in age-related thymic adipogenic mechanism is coupled with maintenance of thymic function. The CR increased cellular density in the thymic cortex and medulla and preserved the epithelial signatures. Interestingly, CR prevented the age-related increase in epithelial-mesenchymal transition (EMT) regulators, FoxC2, and fibroblast-specific protein-1 (FSP-1), together with reduction in lipid-laden thymic fibroblasts. Additionally, CR specifically blocked the age-related elevation of thymic proadipogenic master regulator, peroxisome proliferator activated receptor gamma (PPARgamma), and its upstream activator xanthine-oxidoreductase (XOR). Furthermore, we found that specific inhibition of PPARgamma in thymic stromal cells prevented their adipogenic transformation in an XOR-dependent mechanism. Activation of PPARgamma-driven adipogenesis in OP9-DL1 stromal cells compromised their ability to support T cell development. Conversely, CR-induced reduction in EMT and thymic adipogenesis were coupled with elevated thymic output. Compared with 26-mo-old ad libitum fed mice, the T cells derived from age-matched CR animals displayed greater proliferation and higher IL-2 expression. Furthermore, CR prevented the deterioration of the peripheral TCR repertoire diversity in older animals. Collectively, our findings demonstrate that reducing proadipogenic signaling in thymus via CR may promote thymopoiesis during aging.
The Journal of Immunology 08/2009; 183(5):3040-52. · 5.79 Impact Factor
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ABSTRACT: The adipocytes are the predominant cell types that constitute the bulk of the thymic microenvironment by the fifth decade of life in healthy humans. An age-related increase in thymic adiposity is associated with reduced thymopoiesis and compromised immune surveillance in the elderly. However, the mechanisms regulating the generation of intrathymic adipocytes during aging remain to be elucidated. Here, we report that the CD45- thymic stromal cells (TSCs) are amenable to adipogenesis. We identified that the Wnt inhibitor axin is expressed in the lymphoid as well as stromal cells of the thymus with increased expression in CD45- TSCs of older mice. Knockdown of axin by RNA interference in CD45- primary TSCs led to a marked reduction in adipogenesis with significantly lower expression of adipogenic transcripts peroxisome proliferator-activated receptor 2 (PPAR), adipocyte fatty acid-binding protein (aP2), and perilipin. Age-related elevated axin expression was increased specifically in thymic fibroblasts and medullary thymic epithelial cells (TECs) but not in the cortical TEC or CD45+ cells. Consistent with a role of axin in promoting thymic adipogenesis, axin expression was also colocalized with lipid-expressing adipogenic cells in aging thymus. The prolongevity intervention, caloric restriction (CR), prevented the age-related increase in axin and the adipogenic cell in the thymus together with increase in thymic output. We have recently demonstrated that CR induces ghrelin, which can partially reverse thymic involution. Here, we show that axin expression is not affected by ablation of ghrelin receptors in aging mice, suggesting a ghrelin-independent mechanism for regulation of axin. Our data are consistent with the hypothesis that blocking the specific proadipogenic signals in the thymus may complement the present approaches to rejuvenate thymic function during aging.
Journal of leukocyte biology 04/2009; 85(6):928-38. · 4.99 Impact Factor
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ABSTRACT: Ghrelin (Grln) is a peptide hormone that is predominantly produced in the stomach and stimulates appetite and induces growth hormone (GH) release. We have previously reported that ghrelin is also expressed in T cells and exerts prothymic and anti-inflammatory effects. However, the biologic relevance of T cell-derived ghrelin remains to be determined. Here, we report that acylated-bioactive ghrelin is expressed in human T cells and preferentially segregates within the lipid raft domains upon TCR ligation. The RNA interference (RNAi)-mediated down-regulation of ghrelin in primary human T cells activates IkB, and increases Th1 cytokines and IL-17 secretion. Ghrelin expression declines with increasing age in spleen and T cells and exogenous ghrelin administration in old mice reduces proinflammatory cytokines. These findings demonstrate that ghrelin functions in an autocrine and paracrine capacity to regulate proinflammatory cytokine expression in human and murine T cells and may contribute in regulating "inflamm-aging."
Blood 04/2009; 113(21):5202-5. · 9.90 Impact Factor
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ABSTRACT: With progressive aging, adipocytes are the major cell types that constitute the bulk of thymic microenvironment. Understanding the origin of thymic adipocytes and mechanisms responsible for age-related thymic adiposity is thus germane for the design of long lasting thymic rejuvenation strategies. We have recently identified that ghrelin, an orexigenic anti-inflammatory peptide, can partially reverse age-related thymic involution. Here we demonstrate that Ghrl and ghrelin receptor (growth hormone secretagogue receptor (GHSR)) are expressed in thymic stromal cells and that their expression declines with physiological aging. Genetic ablation of ghrelin and GHSR leads to loss of thymic epithelial cells (TEC) and an increase in adipogenic fibroblasts in the thymus, suggesting potential cellular transitions. Using FoxN1Cre;R26RstopLacZ double transgenic mice, we provide qualitative evidence that thymic epithelial cells can transition to mesenchymal cells that express proadipogenic regulators in the thymus. We found that loss of functional Ghrl-GHSR interactions facilitates EMT and induces thymic adipogenesis with age. In addition, the compromised thymic stromal microenvironment due to lack of Ghrl-GHSR interactions is associated with reduced number of naive T cells. These data suggest that Ghrl may be a novel regulator of EMT and preserves thymic stromal cell microenvironment by controlling age-related adipocyte development within the thymus.
Journal of Biological Chemistry 01/2009; 284(11):7068-77. · 4.77 Impact Factor
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Vishwa Deep Dixit
Journal of Leukocyte Biology 09/2008; 84(4):881. · 4.99 Impact Factor
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Vishwa Deep Dixit
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ABSTRACT: Increasing evidence suggests a tight coupling of metabolic and immune systems. This cross-talk mediated by neuroendocrine peptides as well as numerous cytokines and chemokines is believed to be responsible for integrating energy balance to immune function. These neuroendocrine-immune interactions are heightened during the state of chronic positive energy balance, as seen during obesity, and negative energy balance caused by caloric restriction (CR). Emerging evidence suggests that obesity may be associated with an immunodeficient state and chronic inflammation, which contribute to an increased risk of premature death. The direct interactions between expanded leukocyte populations within the adipose tissue during obesity and an increased number of adipocytes within an aging lymphoid microenvironment may constitute an important adaptive or pathological response as a result of change in energy balance. In stark contrast to obesity, CR causes negative energy balance and robustly prolongs a healthy lifespan in all of the species studied to date. Therefore, the endogenous neuroendocrine-metabolic sensors elevated or suppressed as a result of changes in energy balance may offer an important mechanism in understanding the antiaging and potential immune-enhancing nature of CR. Ghrelin, one such sensor of negative energy balance, is reduced during obesity and increased by CR. Ghrelin also regulates immune function by reducing proinflammatory cytokines and promotes thymopoiesis during aging and thus, may be a new CR mimetic target. The identification of immune effects and molecular pathways used by such orexigenic metabolic factors could offer potentially novel approaches to enhance immunity and increase healthy lifespan.
Journal of Leukocyte Biology 07/2008; 84(4):882-92. · 4.99 Impact Factor
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ABSTRACT: Caloric restriction (CR) is the only preventive intervention that has robust pro-longevity effects in experimental models. Various circulating hormones that regulate the state of negative energy balance may drive the multi-system beneficial effects of the CR phenomenon. Ghrelin, one such stomach-derived circulating peptide hormone stimulates food intake, promotes GH release and inhibits pro-inflammatory cytokines. We have recently demonstrated that ghrelin also reverses age-related thymic involution. Here, we report that chronic CR in aging mice results in reduction in body weight, and spleen size but remarkably, leads to a significant increase in the size and weight of stomach. The increased size of stomach was largely due to increased size of fundus (forestomach) and also smaller but statistically significant enlargement of antrum. The analysis of serial stomach sections revealed that chronic CR leads to a striking hypertrophy of lamina propria, stratum basale, stratum corneum and the stratified squamous epithelium of forestomach of the aged animals. We also report for the first time that chronic CR during aging significantly increases circulating ghrelin levels as well as total ghrelin production in the stomach and reverses age-related loss of ghrelin receptor expression in pituitary. Our data suggests that long-term CR-induced increased ghrelin production from hypertrophic stomach in mice may be an adaptive survival strategy in response to sustained negative energy balance that triggers heightened state of food seeking. Taken together, these data provide new insights into the underlying mechanism behind the salutary effects of chronic caloric restriction during aging process.
Peptides 11/2007; 28(10):1931-6. · 2.43 Impact Factor
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ABSTRACT: The decline in adaptive immunity, T lymphocyte output, and the contraction of the TCR repertoire with age is largely attributable to thymic involution. The loss of thymic function with age may be due to diminished numbers of progenitors and the loss of critical cytokines and hormones from the thymic microenvironment. We have previously demonstrated that the orexigenic hormone ghrelin is expressed by immune cells and regulates T cell activation and inflammation. Here we report that ghrelin and ghrelin receptor expression within the thymus diminished with progressive aging. Infusion of ghrelin into 14-month-old mice significantly improved the age-associated changes in thymic architecture and thymocyte numbers, increasing recent thymic emigrants and improving TCR diversity of peripheral T cell subsets. Ghrelin-induced thymopoiesis during aging was associated with enhanced early thymocyte progenitors and bone marrow-derived Lin(-)Sca1(+)cKit(+) cells, while ghrelin- and growth hormone secretagogue receptor-deficient (GHS-R-deficient) mice displayed enhanced age-associated thymic involution. Leptin also enhanced thymopoiesis in aged but not young mice. Our findings demonstrate what we believe to be a novel role for ghrelin and its receptor in thymic biology and suggest a possible therapeutic benefit of harnessing this pathway in the reconstitution of thymic function in immunocompromised subjects.
Journal of Clinical Investigation 11/2007; 117(10):2778-90. · 15.39 Impact Factor
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ABSTRACT: Originally thought of as a stomach-derived endocrine peptide acting via its receptors in the central nervous system to stimulate food intake and growth hormone expression, ghrelin and its receptor (growth hormone secretagogue receptor (GHS-R)) are widely expressed in a number of organ systems, including cancer cells. However, the direct functional role of ghrelin and its receptor in tumors of central nervous system origin remains to be defined. Here, we demonstrate that the human astrocytoma cell lines U-118, U-87, CCF-STTG1, and SW1088 express 6-, 11-, 15-, and 29-fold higher levels of GHS-R compared with primary normal human astrocytes. The ligation of GHS-R by ghrelin on these cells resulted in an increase in intracellular calcium mobilization, protein kinase C activation, actin polymerization, matrix metalloproteinase-2 activity, and astrocytoma motility. In addition, ghrelin led to actin polymerization and membrane ruffling on cells, with the specific co-localization of the small GTPase Rac1 with GHS-R on the leading edge of the astrocytoma cells and imparting the tumor cells with a motile phenotype. Disruption of the endogenous ghrelin/GHS-R pathway by RNA interference resulted in diminished motility, matrix metalloproteinase activity, and Rac expression, whereas tumor cells stably overexpressing GHS-R exhibited increased cell motility. The relevance of ghrelin and GHS-R expression was verified in clinically relevant tissues from 20 patients with oligodendrogliomas and grade II-IV astrocytomas. Analysis of a central nervous system tumor tissue microarray revealed that strong GHS-R and ghrelin expression was significantly more common in high grade tumors compared with low grade ones. Together, these findings suggest a novel role for the ghrelin/GHS-R axis in astrocytoma cell migration and invasiveness of cancers of central nervous system origin.
Journal of Biological Chemistry 07/2006; 281(24):16681-90. · 4.77 Impact Factor
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ABSTRACT: Vitamin A (VA) deficiency induces a type 1 cytokine response and exogenously provided retinoids can induce a type 2 cytokine response both in vitro and in vivo. The precise mechanism(s) involved in this phenotypic switch are inconsistent and have been poorly characterized in humans. In an effort to determine if retinoids are capable of inducing Th2 cytokine responses in human T cell cultures, we stimulated human PBMCs with immobilized anti-CD3 mAb in the presence or absence of all-trans retinoic acid (ATRA) or 9-cis-RA.
Stimulation of human PBMCs and purified T cells with ATRA and 9-cis-RA increased mRNA and protein levels of IL-4, IL-5, and IL-13 and decreased levels of IFN-gamma, IL-2, IL-12p70 and TNF-alpha upon activation with anti-CD3 and/or anti-CD28 mAbs. These effects were dose-dependent and evident as early as 12 hr post stimulation. Real time RT-PCR analysis revealed a dampened expression of the Th1-associated gene, T-bet, and a time-dependent increase in the mRNA for the Th2-associated genes, GATA-3, c-MAF and STAT6, upon treatment with ATRA. Besides Th1 and Th2 cytokines, a number of additional proinflammatory and regulatory cytokines including several chemokines were also differentially regulated by ATRA treatment.
These data provide strong evidence for multiple inductive roles for retinoids in the development of human type-2 cytokine responses.
BMC Immunology 02/2006; 7:27. · 2.53 Impact Factor
