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Jak2 dampens the induction by IL-1beta 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-1beta of prostaglandin endoperoxide H synthase 2 expression in human orbital fibroblasts: evidence for divergent influence on the prostaglandin E2 biosynthetic pathway



Journal of Immunology 179(10): 7147-7156



ISSN/ISBN: 0022-1767

PMID: 17982107

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.

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Accession: 021232802

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Jak2 Dampens the Induction by Il-1 of Prostaglandin Endoperoxide H Synthase 2 Expression in Human Orbital Fibroblasts: Evidence for Divergent Influence on the Prostaglandin E2 Biosynthetic Pathway. The Journal of Immunology 179(10): 7147-7156, 2007

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