Inhibition of IFN-gamma -induced STAT1 activation by 15- deoxy-Delta 12,14-prostaglandin J2.
The inhibitory actions of 15-deoxy-Delta(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-kappaB. In this study, we have identified an additional signaling pathway sensitive to inhibition by PGJ(2). We show that PGJ(2) 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 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-kappaB 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-kappaB 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 PGJ(2) on IL-1 plus IFN-gamma-stimulated iNOS expression and NO production by beta-cells are persistent for extended periods (< or =48 h). These findings suggest that PGJ(2) 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 PGJ(2) on IL-1 and IFN-gamma signaling in beta-cells.
Weber
Sarah M
SM
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
Scarim
Anna L
AL
Corbett
John A
JA
D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000494:pharmacology* / Q000502:physiology; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000502:physiology*; D014157:Transcription Factors / Q000819:agonists
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D007375:Interleukin-1; D018160:Receptors, Cytoplasmic and Nuclear; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015230:Prostaglandin D2