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

J Clin Invest. 2004 Jul;114(1):57-66. doi: 10.1172/JCI21134.

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-1beta, IL-6, and TNF-alpha. 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.

MeSH terms

  • Cytokines / genetics*
  • Dose-Response Relationship, Drug
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / immunology
  • Ghrelin
  • Human Growth Hormone / pharmacology
  • Humans
  • Inflammation
  • Leptin / antagonists & inhibitors*
  • Leptin / pharmacology*
  • Lymphocyte Activation / drug effects*
  • Monocytes / drug effects
  • Monocytes / immunology*
  • Peptide Hormones / pharmacology*
  • RNA, Messenger / genetics
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / immunology
  • Receptors, G-Protein-Coupled / physiology*
  • Receptors, Ghrelin
  • Receptors, Leptin
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*

Substances

  • Cytokines
  • Ghrelin
  • Leptin
  • Peptide Hormones
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Receptors, Ghrelin
  • Receptors, Leptin
  • leptin receptor, human
  • Human Growth Hormone