Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1.
Prostaglandin E2 Inhibition of IL-27 Production in Murine Dendritic Cells: A Novel Mechanism That Involves IRF1.
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DOI：
10.4049/jimmunol.1601073
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发表时间：
2017-02-15
期刊：
影响因子：
--
通讯作者：
Ganea D
中科院分区：
文献类型：
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作者：
Hooper KM;Yen JH;Kong W;Rahbari KM;Kuo PC;Gamero AM;Ganea D
IL-27是一种由抗原提呈细胞产生的多功能细胞因子，通过影响常规树突状细胞(CDC)、诱导IL-10和促进调节性TR1细胞的发育来抗炎。尽管IL-27诱导的机制已被充分研究，但对负面影响IL-27表达的因素却知之甚少。前列腺素E2(PGE2)是一种主要的免疫调节前列腺素，在多种炎症/自身免疫性疾病模型中起促炎作用，主要促进Th17的发育和功能。在这项研究中，我们报道了一种促进PGE2促炎作用的新机制。我们先前发现PGE2抑制小鼠骨髓来源的DC产生IL-27。在这里，我们发现，除了BMDCs，PGE_2还抑制巨噬细胞和脾CDC中IL-27的产生，我们发现了一种新的途径，包括通过EP2/EP4→诱导cAMP→下调IRF1的表达并与p28ISRE结合。PGE_2对p28和IRF1表达的抑制作用不涉及内源性干扰素β、STAT_1或STAT_2，对IL-27的抑制似乎不是通过PKA、EPAC、PI3K或MAPK介导的。我们在体内观察到二甲基前列腺素E_2与脂多糖联合应用对脾树突状细胞il27p28表达的抑制。基于IL-27在CDC中的抗炎作用，并通过产生TR1细胞，我们认为PGE2诱导的对活化CDC中IL-27的抑制是其体内促炎作用的重要补充机制。
IL-27, a multifunctional cytokine produced by antigen-presenting cells, 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. Prostaglandin E2 (PGE2), a major immunomodulatory prostanoid, acts as a pro-inflammatory agent in several models of inflammatory/autoimmune diseases, promoting primarily Th17 development and function. In this study, we report on a novel mechanism which promotes the pro-inflammatory function of PGE2. We showed previously that PGE2 inhibits IL-27 production in murine bone marrow derived DCs. Here, we show that, in addition to BMDCs, 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 IRF1 expression and binding to the p28 ISRE site. The inhibitory effect of PGE2 on p28 and irf1 expression does not involve endogenous IFNβ, STAT1 or STAT2, and inhibition of IL-27 does not appear to be mediated through PKA, EPAC, 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 pro-inflammatory functions.