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Am J Physiol Endocrinol Metab 284: E883-E891, 2003. First published January 7, 2003; doi:10.1152/ajpendo.00515.2002
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Vol. 284, Issue 5, E883-E891, May 2003

Inhibition of IFN-gamma -induced STAT1 activation by 15- deoxy-Delta 12,14-prostaglandin J2

Sarah M. Weber, Anna L. Scarim, and John A. Corbett

Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri 63104

The inhibitory actions of 15-deoxy-Delta 12,14-prostaglandin J2 (PGJ2) on inflammatory gene expression have been attributed to the ability of this prostaglandin to inhibit the activation of NF-kappa B. In this study, we have identified an additional signaling pathway sensitive to inhibition by PGJ2. We show that PGJ2 inhibits interferon (IFN)-gamma -stimulated phosphorylation and DNA-binding activity of STAT1. The inhibitory actions on STAT1 phosphorylation are first apparent after a 1- to 2-h incubation and are maximal after a 6-h incubation with PGJ2, and they correlate with the expression of heat shock protein (HSP)70 in islets. In previous studies, we have correlated the inhibitory actions of PGJ2 on inducible nitric oxide synthase (iNOS) expression and NF-kappa B activation in response to IL-1 with the increased expression of HSP70. Using overexpression and antisense depletion, we provide evidence that HSP70 does not mediate the inhibitory actions of PGJ2 on IL-1-induced NF-kappa B or IFN-gamma -induced STAT1 activation or cytokine-stimulated iNOS expression by beta -cells. Last, we show that the inhibitory actions of a short 6-h pulse with PGJ2 on IL-1 plus IFN-gamma -stimulated iNOS expression and NO production by beta -cells are persistent for extended periods (<= 48 h). These findings suggest that PGJ2 inhibits multiple cytokine-signaling pathways (IL-1 and IFN-gamma ), that the inhibitory actions are persistent for extended periods, and that increased HSP70 expression correlates with, but does not appear to mediate, the inhibitory actions of PGJ2 on IL-1 and IFN-gamma signaling in beta -cells.

interferon-gamma ; signal transducer and activator of transcription-1; peroxisome proliferator-activated receptor-gamma


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