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J Biol Chem. 2003 Jul 25;278(30):27620-9. Epub 2003 May 15.

Inhibition of interferon (IFN) gamma-induced Jak-STAT1 activation in microglia by vasoactive intestinal peptide: inhibitory effect on CD40, IFN-induced protein-10, and inducible nitric-oxide synthase expression.

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  • 1Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18001, Spain. mdelgado@ipb.csic.es

Abstract

Interferon (IFN)-gamma is one of the most important microglia stimulators in vivo participating in inflammation and Th1 activation/differentiation. IFN-gamma-mediated signaling involves the activation of the Jak/STAT1 pathway. The neuropeptides vasoactive intestinal peptide (VIP) and the pituitary adenylate cyclase activating polypeptide (PACAP) are two potent microglia-deactivating factors that inhibit the production of proinflammatory mediators in vitro and in vivo. The present study investigated the molecular mechanisms involved in the VIP/PACAP regulation of several IFN-gamma-induced microglia-derived factors, including IFN-gamma-inducible protein-10 (IP-10), inducible nitric-oxide synthase (iNOS), and CD40. The results indicate that VIP/PACAP inhibit Jak1-2 and STAT1 phosphorylation, and the binding of activated STAT1 to the IFN-gamma activated site motif in the IFN regulatory factor-1 and CD40 promoter and to the IFN-stimulated response element motif of the IP-10 promoter. Through its effect in the IFN-gamma-induced Jak/STAT1 pathway, VIP and PACAP are able to control the gene expression of IP-10, CD40, and iNOS, three microglia-derived mediators that play an essential role in several pathologies, i.e. inflammation and autoimmune disorders. The effects of VIP/PACAP are mediated through the specific receptor VPAC1 and the cAMP/protein kinase A transduction pathway. Because IFN-gamma is a major stimulator of innate and adaptive immune responses in vivo, the down-regulation of IFN-gamma-induced gene expression by VIP and PACAP could represent a significant element in the regulation of the inflammatory response in the central nervous system by endogenous neuropeptides.

PMID:
12754213
[PubMed - indexed for MEDLINE]
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