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
- Research Support, Non-U.S. Gov't
- Research Support, U.S. Gov't, P.H.S.
MeSH terms
- Animals
- Cytokines / biosynthesis
- Gene Expression
- Inflammation / immunology
- Inflammation / metabolism
- Inflammation / prevention & control*
- Interleukin-10 / genetics
- Interleukin-12 / genetics
- Lipopolysaccharide Receptors / genetics
- Macrophages / drug effects
- Macrophages / immunology
- Macrophages / metabolism
- Mice
- Models, Biological
- Neuropeptides / pharmacology*
- Nitric Oxide / biosynthesis
- Nitric Oxide Synthase / genetics
- Nitric Oxide Synthase Type II
- Pituitary Adenylate Cyclase-Activating Polypeptide
- RNA, Messenger / genetics
- RNA, Messenger / metabolism
- Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
- Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
- Receptors, Pituitary Hormone / drug effects
- Receptors, Pituitary Hormone / genetics
- Receptors, Pituitary Hormone / metabolism*
- Receptors, Vasoactive Intestinal Peptide / drug effects
- Receptors, Vasoactive Intestinal Peptide / genetics
- Receptors, Vasoactive Intestinal Peptide / metabolism*
- Receptors, Vasoactive Intestinal Peptide, Type II
- Receptors, Vasoactive Intestinal Polypeptide, Type I
- Signal Transduction
- Transcription Factors / metabolism*
- Tumor Necrosis Factor-alpha / genetics
- Vasoactive Intestinal Peptide / pharmacology*
Substances
- Adcyap1 protein, mouse
- Adcyap1r1 protein, mouse
- Cytokines
- Lipopolysaccharide Receptors
- Neuropeptides
- Pituitary Adenylate Cyclase-Activating Polypeptide
- RNA, Messenger
- Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
- Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
- Receptors, Pituitary Hormone
- Receptors, Vasoactive Intestinal Peptide
- Receptors, Vasoactive Intestinal Peptide, Type II
- Receptors, Vasoactive Intestinal Polypeptide, Type I
- Transcription Factors
- Tumor Necrosis Factor-alpha
- Vipr1 protein, mouse
- Vipr2 protein, mouse
- Interleukin-10
- Interleukin-12
- Nitric Oxide
- Vasoactive Intestinal Peptide
- Nitric Oxide Synthase
- Nitric Oxide Synthase Type II
- Nos2 protein, mouse