Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells

Dixit, Vishwa Deep; Schaffer, Eric; Pyle, Robert S.; Collins, Gary D.; Sakthivel, Senthil Kumar K.; Palaniappan, Ravichandran; Lillard, James W.; Taub, Dennis D.

doi:10.1172/jci200421134

Cited by 663 publications

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“…We have previously demonstrated that, similar to their opposing metabolic effects on food intake, leptin and ghrelin also exert reciprocal regulatory effects on proinflammatory cytokine production (12). Ghrelin inhibits activation-and leptin-induced proinflammatory cytokine production by human T cells and monocytes (12).…”

Section: And E)mentioning

confidence: 99%

“…Given that ghrelin is expressed and secreted by T cells (12) and that the presence of growth factors in the thymic microenvironment is believed to play a critical role in T cell development (30), we next examined the expression of ghrelin and GHS-R in the thymus of mice of various ages. In comparison with 2-month-old mice, we observed an increase in the expression of thymic ghrelin mRNA in 4-month-old animals, followed by a subsequent decline in both ghrelin and GHS-R expression with progressive thymic aging (Figure 2A).…”

Section: Figurementioning

confidence: 99%

“…We have previously reported that ghrelin inhibits leptin-induced proinflammatory cytokine expression in vitro and in vivo (12). To determine whether there is any possible interaction by leptin in the pro-thymic effects of ghrelin, we also analyzed the circulating leptin levels in vehicle-and ghrelin-infused mice.…”

Section: Figurementioning

confidence: 99%

“…However, additional detailed studies in rodent or primate models are warranted, as long-term neutralization of already suboptimal ghrelin signaling in obesity might be fraught with potentially harmful effects on the thymic output and immune responsiveness to antigenic challenge. Ghrelin inhibits inflammation (12,16), increases GH and appetite, and promotes learning and memory (57) and is therefore proposed as a hormone of significant therapeutic benefit (58). With identification of ghrelin's thymopoietic effects during aging, we propose that harnessing the ghrelin-GHS-R pathway might significantly benefit the aged and immunocompromised host in promoting T cell output and TCR repertoire.…”

Section: Figurementioning

confidence: 99%

“…The ghrelin receptors were traditionally thought be highly expressed in the pituitary and the CNS, but recent studies have identified GHS-Rs in various cells and organs systems including immune cells (11,12). Ghrelin and GHS-R are expressed by peripheral resting and activated human T cells (12) and have been shown to mediate antiinflammatory signals in several cells types (13,14), including mononuclear cells (12,15), and in various murine models of acute and chronic inflammation (13)(14)(15)(16)(17). Involution of thymus is accompanied by replacement of the T cell compartment via infiltration of adipocytes and an increase in proinflammatory cytokines such as IL-6 within the thymic microenvironment (18).…”

Section: Introductionmentioning

confidence: 99%

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Ghrelin promotes thymopoiesis during aging

Dixit¹,

Yang²,

Sun³

et al. 2007

J. Clin. Invest.

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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. IntroductionThe thymus is critical for the development, selection, and maintenance of the peripheral T cell pool possessing a broad spectrum of TCR specificities. The mammalian thymus is capable of generating T cells throughout the life span. However, after puberty and with advancing age, the thymic space becomes progressively filled with adipocytes coupled with a dramatic loss of thymocytes in the cortical and medullary areas, leading to a reduction in output of naive T cells. This process is called as thymic involution (1).The lack of a thymus in humans (DiGeorge syndrome) and thymectomy of neonatal mice lead to severe immunodeficiency due to paucity of mature T cells. During physiological aging, the total peripheral T cell pool is maintained by homeostatic expansion of preexisting T cells rather than replenishment by thymic export (2). Consequently, the long-lived naive T cell repertoire is reduced with an expansion of memory phenotype T cells, thereby limiting a host's ability to mount responses against new antigenic challenges. It has been demonstrated that defects in naive CD4 + T cells are also due to the chronologic age of the naive cells themselves rather than the chronologic age of the host (3). Involution of the thymus with age and lack or paucity of newly formed naive CD4 + T cells is therefore believed to be responsible for much of the deterioration in adaptive immunity and the resultant immune dysfunction in the elderly (4). However, several recent studies have demonstrated that the old thymus still retains the capacity for T cell lymphopoiesis with the ability to mount functional immune responses, albeit to a lim...

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Section: And E)mentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Figurementioning

confidence: 99%