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J. Biol. Chem., Vol. 278, Issue 30, 27620-27629, July 25, 2003

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Inhibition of Interferon (IFN) -induced Jak-STAT1 Activation in Microglia by Vasoactive Intestinal Peptide

INHIBITORY EFFECT ON CD40, IFN-INDUCED PROTEIN-10, AND INDUCIBLE NITRIC-OXIDE SYNTHASE EXPRESSION^*

Mario Delgado 

From the Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Granada 18001, Spain

Interferon (IFN)- is one of the most important microglia stimulators in vivo participating in inflammation and Th1 activation/differentiation. IFN--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--induced microglia-derived factors, including IFN--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- 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--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- is a major stimulator of innate and adaptive immune responses in vivo, the down-regulation of IFN--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.

Received for publication, March 28, 2003 , and in revised form, May 14, 2003.

^* This work was supported by Grant BFI-2002 from the Spanish Department of Science and Technology. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas, Calle Ventanilla, 11, Granada 18001, Spain. Fax: 34-958-203323; E-mail: mdelgado{at}ipb.csic.es.

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