Abstract
VIP and PACAP modulate the function of inflammatory cells through specific receptors. VIP/PACAP inhibit the production of TNF alpha, IL-6, IL-12, and nitric oxide (NO), and stimulate IL-10 in peritoneal macrophages and Raw 264.7 cells. Here we report on the specific VIP/PACAP receptors, transduction pathways, and transcriptional factors involved in the regulation of these macrophage factors by VIP and PACAP. Both neuropeptides inhibit IL-6 production mainly through PAC1 binding, PKC activation, and the subsequent shedding of the LPS receptor CD14 in macrophages. However, the effects on TNF alpha, IL-10, IL-12, and NO are mostly mediated through the constitutively expressed VPAC1 receptor, although the inducible expressed VPAC2 may also participate. VIP/PACAP binding to VPAC1 induces both a cAMP-dependent and a cAMP-independent pathways that regulate cytokine and NO production at the transcriptional level. VIP/PACAP inhibit TNF alpha through reduction in NFkB binding and changes in the composition of CRE-binding complexes; they inhibit IL-12 through reduction in NFkB binding and changes in the composition of the ets-2 complexes. VIP/PACAP inhibit iNOS expression through reduction in NFkB and IRF-1 binding, and augment IL-10 by increasing CREB-binding. Whereas the inhibition of IRF-1 and CRE-binding complexes seems to be mediated through the cAMP-dependent pathway, VIP/PACAP inhibition of NFkB nuclear translocation is mediated through a reduction in IkB alpha degradation mediated by the cAMP-independent pathway. This study provides new evidence for the understanding of the molecular mechanism by means of which VIP and PACAP attenuate the inflammatory response.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cytokines / biosynthesis
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Gene Expression
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Inflammation / immunology
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Inflammation / metabolism
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Inflammation / prevention & control*
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Interleukin-10 / genetics
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Interleukin-12 / genetics
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Lipopolysaccharide Receptors / genetics
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Mice
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Models, Biological
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Neuropeptides / pharmacology*
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Nitric Oxide / biosynthesis
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase Type II
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Pituitary Adenylate Cyclase-Activating Polypeptide
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
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Receptors, Pituitary Hormone / drug effects
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Receptors, Pituitary Hormone / genetics
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Receptors, Pituitary Hormone / metabolism*
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Receptors, Vasoactive Intestinal Peptide / drug effects
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Receptors, Vasoactive Intestinal Peptide / genetics
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Receptors, Vasoactive Intestinal Peptide / metabolism*
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Receptors, Vasoactive Intestinal Peptide, Type II
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Receptors, Vasoactive Intestinal Polypeptide, Type I
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Signal Transduction
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Transcription Factors / metabolism*
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Tumor Necrosis Factor-alpha / genetics
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Vasoactive Intestinal Peptide / pharmacology*
Substances
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Adcyap1 protein, mouse
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Adcyap1r1 protein, mouse
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Cytokines
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Lipopolysaccharide Receptors
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Neuropeptides
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Pituitary Adenylate Cyclase-Activating Polypeptide
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RNA, Messenger
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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
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Receptors, Pituitary Hormone
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Receptors, Vasoactive Intestinal Peptide
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Receptors, Vasoactive Intestinal Peptide, Type II
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Receptors, Vasoactive Intestinal Polypeptide, Type I
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Vipr1 protein, mouse
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Vipr2 protein, mouse
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Interleukin-10
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Interleukin-12
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Nitric Oxide
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Vasoactive Intestinal Peptide
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse