Ghrelin inhibits proinflammatory responses and nuclear factor-kappaB activation in human endothelial cells.

Abstract

BACKGROUND:

Ghrelin is a novel growth hormone-releasing peptide that has been shown to improve cachexia in heart failure and cancer and to ameliorate the hemodynamic and metabolic disturbances in septic shock. Because cytokine-induced inflammation is critical in these pathological states and because the growth hormone secretagogue receptor has been identified in blood vessels, we examined whether ghrelin inhibits proinflammatory responses in human endothelial cells in vitro and after administration of endotoxin to rats in vivo.

METHODS AND RESULTS:

Human umbilical vein endothelial cells (HUVECs) were treated with or without tumor necrosis factor-alpha (TNF-alpha), and induction of proinflammatory cytokines and mononuclear cell adhesion were determined. Ghrelin (0.1 to 1000 ng/mL) inhibited both basal and TNF-alpha-induced cytokine release and mononuclear cell binding. Intravenous administration of ghrelin also inhibited endotoxin-induced proinflammatory cytokine production in rats in vivo. Ghrelin inhibited H2O2-induced cytokine release in HUVECs, suggesting that the peptide blocks redox-mediated cellular signaling. Moreover, ghrelin inhibited basal and TNF-alpha-induced activation of nuclear factor-kappaB. Des-acyl ghrelin had no effect on TNF-alpha-induced cytokine production in HUVECs, suggesting that the antiinflammatory effects of ghrelin require interaction with endothelial growth hormone secretagogue receptors.

CONCLUSIONS:

Ghrelin inhibits proinflammatory cytokine production, mononuclear cell binding, and nuclear factor-kappaB activation in human endothelial cells in vitro and endotoxin-induced cytokine production in vivo. These novel antiinflammatory actions of ghrelin suggest that the peptide could play a modulatory role in atherosclerosis, especially in obese patients, in whom ghrelin levels are reduced.

• Authors: Wei Gen Li, Dan Gavrila, Xuebo Liu, Lixing Wang, Skuli Gunnlaugsson, Lynn L Stoll, Michael L McCormick, Curt D Sigmund, Chaosu Tang, Neal L Weintraub
• Journal: Circulation (Circulation) Vol. 109 Issue 18 Pg. 2221-6 (May 11 2004) ISSN: 1524-4539 [Electronic] United States
• PMID: 15117840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Chemokine CCL2
• Ghrelin
• Interleukin-8
• NF-kappa B
• Peptide Hormones
• Tumor Necrosis Factor-alpha
• ghrelin, des-n-octanoyl
• Hydrogen Peroxide

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Arteriosclerosis (metabolism)
• Cell Adhesion (drug effects)
• Cells, Cultured (drug effects, metabolism)
• Chemokine CCL2 (biosynthesis, genetics)
• Depression, Chemical
• Endothelial Cells (drug effects, metabolism)
• Endothelium, Vascular (cytology, drug effects)
• Endotoxemia (metabolism)
• Gene Expression Regulation (drug effects)
• Genes, Reporter
• Ghrelin
• Humans
• Hydrogen Peroxide (pharmacology)
• Interleukin-8 (biosynthesis, genetics)
• NF-kappa B (metabolism)
• Peptide Hormones (pharmacology)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)
• U937 Cells (drug effects, metabolism)
• Umbilical Veins