新功能、新界面、新体验,扫描即可下载生物谷APP!
首页 » 生物研究 » J immunol: 树突状细胞分泌IL-27的新调节机制

J immunol: 树突状细胞分泌IL-27的新调节机制

来源:生物谷 2017-01-11 10:45


(图片摘自www.sciencealert.com)

2017年1月11日 /生物谷BIOON/ --IL-27是一类IL-12家族的细胞因子,它的两个亚基EBI3与p28能够形成异源二聚体,并通过IL-27R激活下游信号。髓系来源的树突状细胞在受到特定刺激后能够导致TLR、CD40以及IFN 等受体的激活,并最终引发IL-27的分泌。此前也有研究表明DC是IL-27的主要分泌来源。

之前的研究已经证明IL-27在感染性疾病与自体免疫疾病中的作用,IL-27R缺失突变的小鼠水平的试验也表明其能够负向调节T细胞的活性。其中,IL-27被认为能够限制Th1与Th17的分化与功能。尽管IL-27的产生机制已经被研究的十分完善,但负向调控的机制目前并没有得到完全的阐释。

PGE2是一类花生四烯酸的前列腺素,包括DC在内的多种免疫细胞都是其分泌的来源。PGE2通过EP受体能够激活下游信号,从而引起炎症反应。为了研究PGE2在调节DC分泌IL-27过程中的作用,来自美国temple大学的Doina Ganea课题组进行了深入的研究,相关结果发表在最近一期的《Journal of Immunology》杂志上。

首先,作者通过体外实验对小鼠来源的DC进行LPS刺激,并在此基础上进行了PGE2的刺激。结果显示,PGE2能够显著抑制LPS引起的IL-27的分泌,而且存在明显的剂量依赖性。

之后,作者发现PGE2能够结合其特定的受体EP2/EP4,并进一步激活DC胞浆中的cAMP。cAMP的激活能够有效抑制DC表达IL-27。因此,作者认为PGE2能够通过刺激DC表面的受体EP2/EP4以及下游的一系列胞内信号,最终影响IL-27的表达水平。

接下来,作者发现细胞转录因子IRF1参与了PGE2抑制IL-27分泌的这一过程,但STAT1或STAT2则没有参与这一过程。

最后,作者还通过体外实验证明了IFN-beta也一定程度上参与了这一信号的调节过程。

综上,作者通过一系列体外实验阐释了PGE2负向调节IL-27分泌的分子机制。(生物谷Bioon.com)

本文系生物谷原创编译整理,欢迎转发,转载需授权!点击 获取授权 。更多资讯请下载生物谷app.



PMC:

PMID:

Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1

Kirsten M. Hooper, Jui-Hung Yen, Weimin Kong, Kate M. Rahbari, Ping-Chang Kuo, Ana M. Gamero and Doina Ganea

IL-27, a multifunctional cytokine produced by APCs, antagonizes inflammation by affecting conventional dendritic cells (cDC), inducing IL-10, and promoting development of regulatory Tr1 cells. Although the mechanisms involved in IL-27 induction are well studied, much less is known about the factors that negatively impact IL-27 expression. PGE2, a major immunomodulatory prostanoid, acts as a proinflammatory agent in several models of inflammatory/autoimmune disease, promoting primarily Th17 development and function. In this study, we report on a novel mechanism that promotes the proinflammatory function of PGE2. We showed previously that PGE2 inhibits IL-27 production in murine bone marrow-derived DCs. In this study, we show that, in addition to bone marrow-derived DCs, PGE2 inhibits IL-27 production in macrophages and in splenic cDC, and we identify a novel pathway consisting of signaling through EP2/EP4→induction of cAMP→downregulation of IFN regulatory factor 1 expression and binding to the p28 IFN-stimulated response element site. The inhibitory effect of PGE2 on p28 and irf1 expression does not involve endogenous IFN-β, STAT1, or STAT2, and inhibition of IL-27 does not appear to be mediated through PKA, exchange protein activated by cAMP, PI3K, or MAPKs. We observed similar inhibition of il27p28 expression in vivo in splenic DC following administration of dimethyl PGE2 in conjunction with LPS. Based on the anti-inflammatory role of IL-27 in cDC and through the generation of Tr1 cells, we propose that the PGE2-induced inhibition of IL-27 in activated cDC represents an important additional mechanism for its in vivo proinflammatory functions.

温馨提示:87%用户都在生物谷APP上阅读,扫描立刻下载! 天天精彩!


相关标签

最新会议 培训班 期刊库