Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells
Vishwa Deep Dixit, … , James W. Lillard Jr., Dennis D. Taub
Vishwa Deep Dixit, … , James W. Lillard Jr., Dennis D. Taub
Published July 1, 2004
Citation Information: J Clin Invest. 2004;114(1):57-66. https://doi.org/10.1172/JCI21134.
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Article Immunology

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

Abstract

Ghrelin, a recently described endogenous ligand for the growth hormone secretagogue receptor (GHS-R), is produced by stomach cells and is a potent circulating orexigen, controlling energy expenditure, adiposity, and growth hormone secretion. However, the functional role of ghrelin in regulation of immune responses remains undefined. Here we report that GHS-R and ghrelin are expressed in human T lymphocytes and monocytes, where ghrelin acts via GHS-R to specifically inhibit the expression of proinflammatory anorectic cytokines such as IL-1β, IL-6, and TNF-α. Ghrelin led to a dose-dependent inhibition of leptin-induced cytokine expression, while leptin upregulated GHS-R expression on human T lymphocytes. These data suggest the existence of a reciprocal regulatory network by which ghrelin and leptin control immune cell activation and inflammation. Moreover, ghrelin also exerts potent anti-inflammatory effects and attenuates endotoxin-induced anorexia in a murine endotoxemia model. We believe this to be the first report demonstrating that ghrelin functions as a key signal, coupling the metabolic axis to the immune system, and supporting the potential use of ghrelin and GHS-R agonists in the management of disease-associated cachexia.

Authors

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

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Ghrelin is expressed and secreted from human T cells. (A) Ghrelin and GH...
Ghrelin is expressed and secreted from human T cells. (A) Ghrelin and GHS-R coexpression in resting T cells (upper row); activated T cells demonstrating that ghrelin is strongly colocalized in GM1+ lipid rafts (middle row); preproghrelin colocalizes in Golgi bodies in activated human T cells (lower row). (B) Kinetics of ghrelin secretion from anti-CD3 mAb–stimulated T cells. (C) Fold change in ghrelin mRNA levels upon T cell activation as assessed by real time RT-PCR analysis. Values are expressed as mean ± SEM (*P < 0.05). (D) Ghrelin expression was quantitated in T cells stimulated in presence of immobilized anti-CD3 antibody and in the presence or absence of different concentrations of leptin after 24 hours in culture. Fold change in ghrelin mRNA expression (black bars) after normalization with GAPDH and measured by real time RT-PCR. Ghrelin protein production was determined by EIA (white bars). (E) Fold change in GHS-R gene expression after normalization with GAPDH (n = 6), with values expressed as mean ± SEM (*P < 0.05). (F) Hypothetical model for functional role of ghrelin as a signal linking the immune and endocrine systems in control of food intake. (G) Comparative ghrelin mRNA expression in stomach as compared to lymphoid organs. SI, small intestine.