Jak2 dampens the induction by IL-1β of prostaglandin endoperoxide H synthase 2 expression in human orbital fibroblasts:: Evidence for divergent influence on the prostaglandin E2 biosynthetic pathway
Jak2 dampens the induction by IL-1β of prostaglandin endoperoxide H synthase 2 expression in human orbital fibroblasts:: Evidence for divergent influence on the prostaglandin E2 biosynthetic pathway
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DOI：
10.4049/jimmunol.179.10.7147
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发表时间：
2007-11-15
影响因子：
4.4
通讯作者：
Smith, Terry J.
中科院分区：
文献类型：
--
作者：
Han, Rui;Chen, Beiling;Smith, Terry J.
前列腺素内源性过氧化氢合成酶2(PGHS-2)催化前列腺素E(2)合成的限速步骤。在用IL-1β处理的人眼眶成纤维细胞中，它实质上是诱导的，但是短暂的。在这项研究中，我们报告了当JAK2信号被取消时，IL-1β诱导PGHS-2的作用显著增强和延长，无论是用特定的抑制剂AG490还是通过瞬时转染显性负突变JAK2的成纤维细胞。减弱JAK2可增加PGHS-2的稳态mRNA水平，这是IL-1β处理的培养物中基因转录和mRNA存活增加的结果。令人惊讶的是，JAK2功能的中断也阻断了通常由IL-1β引起的PGE2合成的预期增加。这是由于IL-1β依赖的花生四烯酸释放迅速丧失以及IIA组分泌的PLA2(2)(SPLA2)基因诱导的减弱所致。给予JAK2受损的培养物外源花生四烯酸未能增加PGE2的产量，以响应IL-1β，直到细胞被机械破坏。然而，将野生型Spla瞬时转染后，前列腺素的产量完全恢复到预期的水平。SPLA2的表达导致IL-1β依赖的PGHS-2和微粒体PGE2合成酶水平增加。因此，除了释放花生四烯酸外，Spla在PGE(2)的合成中也起着重要的作用。我们的发现表明，JAK2通常会抑制和限制IL-1β诱导PGHS-2的持续时间。此外，它是IL-1β依赖的信号转导SplA(2)所必需的，它的表达和活性是上调眼眶成纤维细胞合成PGE2所必需的。
Prostaglandin endoperoxide H synthase 2 (PGHS-2) catalyzes the rate-limiting steps in the synthesis of PGE(2). It is substantially but transiently induced in human orbital fibroblasts treated with IL-1 beta. In this study, we report that the induction of PGHS-2 by IL-1 beta is dramatically enhanced and prolonged when Jak2 signaling is abrogated, either with the specific inhibitor AG490 or by transiently transfecting fibroblasts with a dominant negative mutant Jak2. Attenuating Jak2 increases PGHS-2 steady-state mRNA levels, a consequence of increased gene transcription and mRNA survival in IL-1 beta-treated cultures. Surprisingly, interrupting Jak2,function also blocked the expected increase in PGE2 synthesis usually provoked by IL-1 beta. This resulted from the rapid loss of IL-1 beta-dependent arachidonate release and by attenuation of group IIA secreted PLA(2) (sPLA(2)) gene induction. Supplying Jak2-compromised cultures with exogenous arachidonate failed to increase PGE2 production in response to IL-1 beta until cells were mechanically disrupted. However, transiently transfecting them with wild-type sPLA, fully restored prostanoid production to anticipated levels. sPLA2 expression following transfection resulted in increased IL-1 beta-dependent PGHS-2 and microsomal PGE2 synthase levels. Thus, sPLA, plays important roles in PGE(2) synthesis in addition to its release of arachidonate. Our findings suggest that Jak2 ordinarily dampens and limits the duration of the PGHS-2 induction by IL-1 beta. Moreover, it is required for IL-1 beta-dependent signaling to sPLA(2), the expression and activity of which are necessary for up-regulating PGE2 synthesis in orbital fibroblasts.