HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Han, R. Articles by Smith, T. J. Search for Related Content PubMed PubMed Citation Articles by Han, R. Articles by Smith, T. J.

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 Pathway¹

Department of Medicine, Division of Molecular Medicine, Harbor-University of California Los Angeles Medical Center, Torrance, CA 90502 and the David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095

Prostaglandin endoperoxide H synthase 2 (PGHS-2) catalyzes the rate-limiting steps in the synthesis of PGE₂. It is substantially but transiently induced in human orbital fibroblasts treated with IL-1β. In this study, we report that the induction of PGHS-2 by IL-1β 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-1β-treated cultures. Surprisingly, interrupting Jak2 function also blocked the expected increase in PGE₂ synthesis usually provoked by IL-1β. This resulted from the rapid loss of IL-1β-dependent arachidonate release and by attenuation of group IIA secreted PLA₂ (sPLA₂) gene induction. Supplying Jak2-compromised cultures with exogenous arachidonate failed to increase PGE₂ production in response to IL-1β until cells were mechanically disrupted. However, transiently transfecting them with wild-type sPLA₂ fully restored prostanoid production to anticipated levels. sPLA₂ expression following transfection resulted in increased IL-1β-dependent PGHS-2 and microsomal PGE₂ synthase levels. Thus, sPLA₂ plays important roles in PGE₂ 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-1β. Moreover, it is required for IL-1β-dependent signaling to sPLA₂, the expression and activity of which are necessary for up-regulating PGE₂ synthesis in orbital fibroblasts.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by National Institutes of Health Grants EY008976, EY011708, DK063121, and RR00425. We gratefully acknowledge generous support from the Bell Charitable Foundation.

² R.H. and B.C. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Terry J. Smith, Division of Molecular Medicine, Building C-2, Harbor-University of California Los Angeles Medical Center, 1124 West Carson Street, Torrance, CA 90502. E-mail address: tjsmith{at}ucla.edu

⁴ Abbreviations used in this paper: sPLA₂, secreted phospholipase A₂; cPLA₂, cytoplasmic PLA₂; mPGES, microsomal PLA₂ synthase; PGHS, PG endoperoxide H synthase; DN, dominant negative; DRB, 5,6-dichlorobenzimidazole; TAO, thyroid-associated ophthalmopathy; EIA, enzyme immunoassay; UTR, untranslated region; AU, arbitrary unit.