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B and IFN Regulatory Factor 1 Activation1
*
Department of Biological Sciences, Rutgers University, Newark, NJ 07102; and
Departamento Biologia Celular, Universidad Complutense, 28040 Madrid, Spain
High-output nitric oxide (NO) production from activated
macrophages, resulting from the induction of inducible NO synthase
(iNOS) expression, represents a major mechanism for macrophage
cytotoxicity against pathogens. However, despite its beneficial role in
host defense, sustained high-output NO production was also implicated
in a variety of acute inflammatory diseases and autoimmune diseases.
Therefore, the down-regulation of iNOS expression during an
inflammatory process plays a significant physiological role. This study
examines the role of two immunomodulatory neuropeptides, the vasoactive
intestinal peptide (VIP) and the pituitary adenylate cyclase-activating
polypeptide (PACAP), on NO production by LPS-, IFN-
-, and
LPS/IFN--stimulated peritoneal macrophages and the Raw 264.7 cell
line. Both VIP and PACAP inhibit NO production in a dose- and
time-dependent manner by reducing iNOS expression at protein and mRNA
level. VPAC1, the type 1 VIP receptor, which is constitutively
expressed in macrophages, and to a lesser degree VPAC2, the type 2 VIP
receptor, which is induced upon macrophage activation, mediate the
effect of VIP/PACAP. VIP/PACAP inhibit iNOS expression and activity
both in vivo and in vitro. Two transduction pathways appear to be
involved, a cAMP-dependent pathway that preferentially inhibits IFN
regulatory factor-1 transactivation and a cAMP-independent pathway that
blocks NF-
B binding to the iNOS promoter. The down-regulation of
iNOS expression, together with previously reported inhibitory effects
on the production of the proinflammatory cytokines IL-6, TNF-
, and
IL-12, and the stimulation of the anti-inflammatory IL-10, define
VIP and PACAP as "macrophage deactivating factors" with significant
physiological relevance.
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