Inhibition of IFN-γ-induced STAT1 activation by 15- deoxy-Δ 12,14 -prostaglandin J 2

The inhibitory actions of 15-deoxy-Δ 12,14 -prostaglandin J 2 (PGJ 2 ) on inflammatory gene expression have been attributed to the ability of this prostaglandin to inhibit the activation of NF-κB. In this study, we have identified an additional signaling pathway sensitive to inhibition by PGJ 2 . We show that PGJ 2 inhibits interferon (IFN)-γ-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 PGJ 2 , and they correlate with the expression of heat shock protein (HSP)70 in islets. In previous studies, we have correlated the inhibitory actions of PGJ 2 on inducible nitric oxide synthase (iNOS) expression and NF-κB 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 PGJ 2 on IL-1-induced NF-κB or IFN-γ-induced STAT1 activation or cytokine-stimulated iNOS expression by β-cells. Last, we show that the inhibitory actions of a short 6-h pulse with PGJ 2 on IL-1 plus IFN-γ-stimulated iNOS expression and NO production by β-cells are persistent for extended periods (≤48 h). These findings suggest that PGJ 2 inhibits multiple cytokine-signaling pathways (IL-1 and IFN-γ), 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 PGJ 2 on IL-1 and IFN-γ signaling in β-cells.