Lipopolysaccharide induces calcitonin gene-related peptide in the RAW264.7 macrophage cell line
Lipopolysaccharide induces calcitonin gene-related peptide in the RAW264.7 macrophage cell line
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DOI：
10.1111/j.1365-2567.2009.03239.x
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发表时间：
2010-07-01
期刊：
影响因子：
6.4
通讯作者：
Quirion, Remi
中科院分区：
文献类型：
--
作者：
Ma, Weiya;Dumont, Yvan;Quirion, Remi
降钙素基因相关肽(CGRP)分布广泛，在多种生物学功能中发挥重要作用。它富含初级感觉神经元，因此与伤害性感受和神经源性炎症有关。最近的研究表明，CGRP可由单核/巨噬细胞等免疫细胞在炎症刺激下产生，提示CGRP在先天免疫中起作用。然而，目前尚不清楚CGRP在巨噬细胞中是如何上调的，以及它是否在巨噬细胞的功能中发挥作用，如细胞因子和趋化因子的产生。应用酶联免疫吸附试验和多重酶联免疫吸附试验，发现脂多糖可诱导RAW-264.7巨噬细胞系CGRP的表达。内毒素诱导的炎症介质如神经生长因子(NGF)、白介素1β(IL-1β)、IL-6、前列腺素E-2(PGE(2))和核因子-kappaB(NF-kappa B)信号参与了CGRP的诱导，而NGF受体TrkA和CGRP受体信号通路出人意料地参与抑制LPS诱导的CGRP，从而导致CGRP释放的微调调节。外源性CGRP及其受体拮抗剂对基础或脂多糖诱导的巨噬细胞释放单核细胞趋化蛋白-1、IL-1β、IL-6、肿瘤坏死因子-α和IL-10均有浓度依赖性的刺激、抑制或无作用。CGRP受体信号通路依赖于配体浓度调节炎症介质的产生，是CGRP刺激和抑制免疫和炎症反应的一种新机制。总之，我们的数据表明，单核/巨噬细胞是降钙素基因相关肽的重要来源。炎症诱导的CGRP对其他促炎和抗炎介质的产生有积极或消极的交互作用。因此，CGRP在免疫和炎症反应中既有促进作用，也有抑制作用。
P>Calcitonin gene-related peptide (CGRP) is widely distributed and plays important roles in a wide array of biological functions. It is enriched in primary sensory neurons and hence involved in nociception and neurogenic inflammation. Recent studies have shown that CGRP can be produced by immune cells such as monocytes/macrophages following inflammatory stimulation, suggesting a role in innate immunity. However, it is unclear how CGRP is up-regulated in macrophages and if it plays a role in macrophage functions such as the production of cytokines and chemokines. Using enzyme-linked immunosorbent assay (ELISA) and multiplex ELISA, lipopolysaccharide (LPS) was found to induce CGRP in the RAW 264.7 macrophage cell line. LPS-induced inflammatory mediators such as nerve growth factor (NGF), interleukin-1 beta (IL-1 beta), IL-6, prostaglandin E-2 (PGE(2)) and nuclear factor-kappa B (NF-kappa B) signalling are involved in inducing CGRP, whereas the NGF receptor trkA and CGRP receptor signalling pathways are unexpectedly involved in suppressing LPS-induced CGRP, which leads to the fine-tune regulation of CGRP release. Exogenous CGRP and CGRP receptor antagonists, in a concentration-dependent manner, stimulated, inhibited or had no effect on basal or LPS-induced release of monocyte chemoattractant protein-1, IL-1 beta, IL-6, tumour necrosis factor-alpha and IL-10 in RAW macrophages. The ligand-concentration-dependent regulation of the production of inflammatory mediators by CGRP receptor signalling is a novel mechanism underlying the stimulating and suppressing role of CGRP in immune and inflammatory responses. Together, our data suggest that monocytes/macrophages are an important source of CGRP. Inflammation-induced CGRP has a positive or negative reciprocal effect on the production of other pro- and anti-inflammatory mediators. Thereby CGRP plays both facilitating and suppressing roles in immune and inflammatory responses.