Reduction of T cell–derived ghrelin enhances proinflammatory cytokine expression: implications for age-associated increases in inflammation

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 downregulation 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 "inflammaging." (Blood. 2009;113:5202-5205) IntroductionGhrelin, originally thought to be stimulator of GH axis 1 and food intake 2 also exerts potent inhibitory effects on proinflammatory mediators via its action on T cells, monocytes, 3-5 and endothelial cells. 6 Recent evidence suggests that leptin, which inhibits food intake, 7 can promote inflammation 3,8 and is also produced from T cells. 8,9 Interestingly, leptin neutralization in T cells with monoclonal antibodies promotes regulatory T cell (Treg) proliferation 9 and protects against experimental autoimmune encephalomyelitis (EAE). 8 Many previous reports suggest that apart from cytokines and chemokines, T cells may also express certain hormones. 10,11 Emerging evidence supports this long-held view that ligands and receptors of neuroendocrine origin may also directly regulate immune function. 3,9 We have recently shown that ghrelin is also expressed and secreted by T cells 3 and its expression declines in the thymus with age. 12 In addition, mice with ablation of ghrelin and ghrelin-receptor (GHSR) display accelerated thymic involution, whereas ghrelin supplementation promotes thymopoiesis in aged mice 12 and protects against sepsis. 3 In this study, we tested the hypothesis that the bioactive ghrelin within T cells serves as a regulator of proinflammatory cytokines and investigated whether T cell-expressed ghrelin is functionally significant. Methods Human subjects and T-cell isolationPheresis packs were prepared from 6 healthy male donors between the age of 30 and 45 years age and T cells were isolated as described previously. 3 For primary T cells, leukapheresis packs were acquired from healthy human volunteers from whom informed consent was obtained in accordance with the Declaration of Helsinki. Mice and ghrelin infusionsBalb/c mice were maintained under the specific pathogen-free conditions of the National Institute on Aging (NIA) animal facility using protocols approved by the animal care and use committee of the NIA Intramural Research Program located i...

Effect of acute and regular exercise on growth hormone secretagogue receptor-1a expression in human lymphocytes, T cell subpopulation and monocytes

“…Indeed ghrelin and GHS-R1a knockout mice exhibit reduced thymocyte counts and more pronounced age-dependent thymic involution than in wild type mice (Dixit et al, 2007). Ghrelin expression by T cells is also reduced in ageing mice and ghrelin infusion in this model has been shown to reduce levels of IL-6, TNF-α and IL-1β (Dixit et al, 2009). Ghrelin infusion to improve lean body mass and appetite and decrease circulating inflammatory cytokines has had positive outcomes in patient populations with inflammation-related cachexia including cachetic cancer, cardiovascular disease, chronic obstructive pulmonary disease and chronic kidney disease (DeBoer, 2011;DeBoer et al, 2008;Nagaya et al, 2004Nagaya et al, , 2005Strasser et al, 2008).…”

“…Immune cell expression of GHS-R1a declines with age and has been related to age-associated thymic involution and increased levels of systemic inflammation (Dixit and Taub, 2005;Dixit et al, 2009). Indeed ghrelin and GHS-R1a knockout mice exhibit reduced thymocyte counts and more pronounced age-dependent thymic involution than in wild type mice (Dixit et al, 2007).…”

“…However, both acylated and des-acylated ghrelin are also secreted by human monocytes and T cells, with secretion increasing rapidly upon activation and peaking after 48 h (Hattori et al, 2001, Dixit et al, 2004Dixit et al, 2009). The amount secreted is not insignificant; activated T cells can produce between 300 and 800 pg.ml -1 of total ghrelin upon activation and can also express the pre-pro form of ghrelin in their Golgi bodies, where it is presumably cleaved to its mature form (Dixit et al, 2004).…”

Immunotherapy of Immunosenesence; Who, How and When?

“…Along with GH and IGF-1, the peptide hormone ghrelin, principally known to induce GH by binding through the growth hormone secretagogue receptor (GHS-R), has been reported to enhance thymopoiesis in aged mice [36]. In addition, ghrelin is able to repress inflamm-aging, that in turn would contribute to the enhanced T cell reconstitution observed in older mice [37].…”

The effects of exercise on macrophage function

“…Recently, new evidence has pointed toward the potential role of ghrelin in influencing the immune system. This observation includes both in vitro and in vivo data indicating that ghrelin receptors are present in leukocytes, that some leukocytes endogenously produce ghrelin (e.g., T cells and human PBMCs), and that the exogenous administration of ghrelin may ameliorate pathologic inflammatory conditions 65,66) . Ghrelin is currently known to be the only endocrine hormone that stimulates food intake and meal initiation 67) .…”