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Am J Physiol Endocrinol Metab (January 7, 2003). doi:10.1152/ajpendo.00515.2002
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Submitted on November 22, 2002
Accepted on December 14, 2002

Inhibition of IFN-{gamma}-induced STAT-1 activation by 15-deoxy-{Delta} 12, 14 - Prostaglandin J2

Sarah M. Weber1, Anna L. Scarim1, and John A. Corbett1*

1 Edward A. Doisey Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, USA

* To whom correspondence should be addressed. E-mail: corbettj{at}slu.edu.

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 nuclear factor (NF)-{kappa}B. In this study we have identified an additional signaling pathway sensitive to inhibition by PGJ2. We show that PGJ2 inhibits INF-{gamma}-stimulated phosphorylation and DNA binding activity of signal transducer and activator of transcription (STAT)-1. The inhibitory actions on STAT-1 phosphorylation are first apparent following 1-2 h incubation and maximal following 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 hsp 70. Using overexpression and antisense depletion, we provide evidence that hsp 70 does not mediate the inhibitory actions of PGJ2 on IL-1-induced NF-{kappa}B or IFN-{gamma}-induced STAT-1 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 + IFN-{gamma}-stimulated iNOS expression and nitric oxide production by {beta}-cells are persistent for extended periods (as long as 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 hsp 70 expression correlates with, but does not appear to mediate, the inhibitory actions of PGJ2 on IL-1 and IFN-{gamma} signaling in {beta}-cells.




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