外源性胃饥饿素通过不同的信号通路调节脂多糖刺激的巨噬细胞中促炎和抗炎细胞因子的释放。

Exogenous ghrelin modulates release of pro-inflammatory and anti-inflammatory cytokines in LPS-stimulated macrophages through distinct signaling pathways.

作者信息

Waseem Talat, Duxbury Mark, Ito Hiromichi, Ashley Stanley W, Robinson Malcolm K

机构信息

Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass 02115, USA.

出版信息

Surgery. 2008 Mar;143(3):334-42. doi: 10.1016/j.surg.2007.09.039. Epub 2007 Dec 27.

DOI:10.1016/j.surg.2007.09.039

PMID:18291254

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2278045/

Abstract

BACKGROUND

Ghrelin, an orexigenic 28-amino-acid peptide, has been studied primarily in relation to the control of appetite and fat metabolism. In addition to these well-known functions, ghrelin, and its target receptors, growth hormone secretagogue receptors (GHS-Rs), have been localized to neutrophils, lymphocytes, and macrophages, which suggests that ghrelin may be involved in immune modulation.

METHODS

To assess the therapeutic role of ghrelin in production of pro-inflammatory and anti-inflammatory cytokines, the effects of exogenous ghrelin administration on the regulation of cytokine release in lipopolysaccharide (LPS)-activated murine RAW 264.7 macrophages were analyzed.

RESULTS

Ghrelin and GHS-Rs are expressed in murine macrophages. In addition, exogenous ghrelin inhibited the production of pro-inflammatory cytokines IL-1beta and TNF-alpha in LPS-stimulated murine macrophages in a dose dependent and time-dependent fashion. Exogenous ghrelin pretreatment resulted in a decrease in LPS-induced NFkappaB activation and was presumably the reason for this ghrelin-mediated effect. In contrast to these findings, exogenous ghrelin significantly augmented the release of the anti-inflammatory cytokine IL-10 in a dose-dependent and time-dependent fashion from LPS-stimulated murine macrophages. Ghrelin administration enhanced activation of p38 MAPK, which is known to control the release of IL-10 in macrophages independent of the NFkappaB pathway. These effects of ghrelin on both pro-inflammatory and anti-inflammatory cytokines were offset when a specific GHS-R receptor antagonist was added to the culture media.

CONCLUSIONS

These data suggest that ghrelin has potent anti-inflammatory properties through modulation of secretion of both pro-inflammatory and anti-inflammatory cytokines from LPS-stimulated macrophages through distinct signaling cascades. Therapeutic utility of ghrelin to control, modulate, or treat pathologic inflammatory conditions like endotoxemic shock and ulcerative colitis requires additional investigation.

摘要

背景

胃饥饿素是一种具有促食欲作用的28个氨基酸的肽，主要围绕食欲控制和脂肪代谢进行研究。除了这些广为人知的功能外，胃饥饿素及其靶受体——生长激素促分泌素受体（GHS-Rs），已在中性粒细胞、淋巴细胞和巨噬细胞中定位，这表明胃饥饿素可能参与免疫调节。

方法

为评估胃饥饿素在促炎和抗炎细胞因子产生中的治疗作用，分析了外源性给予胃饥饿素对脂多糖（LPS）激活的小鼠RAW 264.7巨噬细胞中细胞因子释放调节的影响。

结果

胃饥饿素和GHS-Rs在小鼠巨噬细胞中表达。此外，外源性胃饥饿素以剂量和时间依赖性方式抑制LPS刺激的小鼠巨噬细胞中促炎细胞因子IL-1β和TNF-α的产生。外源性胃饥饿素预处理导致LPS诱导的NFκB激活减少，这可能是胃饥饿素介导该效应的原因。与这些发现相反，外源性胃饥饿素以剂量和时间依赖性方式显著增加LPS刺激的小鼠巨噬细胞中抗炎细胞因子IL-10的释放。给予胃饥饿素增强了p38 MAPK的激活，已知p38 MAPK可独立于NFκB途径控制巨噬细胞中IL-10的释放。当向培养基中添加特异性GHS-R受体拮抗剂时，胃饥饿素对促炎和抗炎细胞因子的这些作用被抵消。