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Division of Molecular Medicine, Department of Medicine, Harbor-University of California, Los Angeles, Medical Center, Torrance, California 90502; and the David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095
Address all correspondence and requests for reprints to: Terry J. Smith, M.D., Division of Molecular Medicine, Building C-2, Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, California 90502. E-mail: tjsmith{at}ucla.edu.
Thyroid-associated ophthalmopathy (TAO) is an autoimmune component of Graves’ disease characterized by intense inflammation in the setting of volume expansion. At the heart of orbital susceptibility to Graves’ disease appears to be the peculiar phenotype of orbital fibroblasts that, when activated by IL-1ß and other proinflammatory cytokines, produce excess prostaglandin E2 (PGE2) and hyaluronan. T helper type 1 (Th1) cytokines predominate early in TAO, whereas Th2 cytokines are more abundant later. It is currently unknown whether this transition might promote changes in tissue reactivity associated with disease progression. We report here that interferon-
and IL-4, representative of these respective classes of cytokines, attenuate IL-1ß-provoked PGE2 production. This down-regulation is mediated by blocking the induction of prostaglandin endoperoxide H synthase-2 (PGHS-2), the inflammatory cyclooxygenase. The mechanism involves blockade by IL-4 and interferon- of the IL-1ß-dependent activation of PGHS-2 gene promoter activity. In addition, interferon inhibits IL-1ß-provoked PGHS-2 mRNA stability. The actions of interferon- and IL-4 are mediated through the Janus kinase 2/signal transducer and activator of transcription signaling pathway and could be abolished by treating with AG490, a specific inhibitor of Janus kinase 2. In contrast, the up-regulation of hyaluronan synthesis by IL-1ß is enhanced by either IL-4 or interferon-. The latter two cytokines enhance the induction by IL-1ß of hyaluronan synthase-2 expression. These unexpected findings indicate that the Th1
Th2 cytokine transition exerts equivalent influence on PGE2 and hyaluronan production as TAO progresses from early to late stage.
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