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J. Biol. Chem., Vol. 281, Issue 27, 18296-18306, July 7, 2006

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Interleukin-4 Induces 15-Lipoxygenase-1 Expression in Human Orbital Fibroblasts from Patients with Graves Disease

EVIDENCE FOR ANATOMIC SITE-SELECTIVE ACTIONS OF Th2 CYTOKINES^*

Beiling Chen¹, Shanli Tsui, William E. Boeglin^¶, Raymond S. Douglas, Alan R. Brash^¶, and Terry J. Smith²

From the Division of Molecular Medicine, Department of Medicine, Harbor-UCLA Medical Center, Torrance, California 90502, the David Geffen School of Medicine at UCLA, Los Angeles, California 90095, and the ^¶Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Orbital fibroblasts orchestrate tissue remodeling in Graves disease, at least in part, because they exhibit exaggerated responses to proinflammatory cytokines. A hallmark of late stage orbital disease is vision-threatening fibrosis, the molecular basis of which remains uncertain. We report here that the Th2 cytokines, interleukin (IL)-4 and IL-13, can induce in these cells the expression of 15-lipoxygenase-1 (15-LOX-1) and in so doing up-regulate the production of 15-hydroxyeicosatetraenoic acid. IL-4 increases 15-LOX-1 protein levels through pretranslational actions. The increased steady-state 15-LOX-1 mRNA is independent of ongoing protein synthesis and involves very modestly increased gene promoter activity. Importantly, IL-4 substantially enhances 15-LOX-1 transcript stability, activity that localizes to a 293-bp sequence of the 3'-untranslated region. IL-4 activates Jak2 in orbital fibroblasts. Interrupting signaling through that pathway, either with the specific chemical inhibitor, AG490, or by transiently transfecting the cells with a Jak2 dominant negative mutant kinase, attenuates the 15-LOX-1 induction. Interferon, a Th1 cytokine, could block this induction by attenuating IL-4-dependent mRNA stabilization. 15-LOX-1 protein and its mRNA were undetectable in IL-4-treated dermal fibroblasts, despite comparable levels of cell surface IL-4 receptor and phosphorylated Jak2 and STAT6. Our findings suggest that orbital connective tissues may represent a site of localized 15-hydroxyeicosatetraenoic acid generation resulting from cell type-specific 15-LOX-1 mRNA stabilization by IL-4. These results may have relevance to the pathogenesis of orbital Graves disease, an inflammatory autoimmune condition that gives way to extensive fibrosis associated with a Th2 response.

Received for publication, April 11, 2006

^* This work was supported in part by National Institutes of Health Grants EY008976, EY011708, DK063121, RR00425, EY016339, GM53638, and GM15431 and by Steve and Kathleen Flynn and the Bell Charitable Foundation. 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 Supported by the largess of Dr. Steve Liu and the late Dr. Milly Liu.

² To whom correspondence should be addressed: Division of Molecular Medicine, Bldg. C-2, Harbor-UCLA Medical Center, 1124 W. Carson St., Torrance, CA 90502. Tel.: 310-222-3691; Fax: 310-222-6820; E-mail: tjsmith{at}ucla.edu.

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