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Receptors and Transcriptional Factors Involved in the Anti‐Inflammatory Activity of VIP and PACAP
Author(s) -
LECETA JAVIER,
GOMARIZ ROSA P.,
MARTINEZ CARMEN,
ABAD CATALINA,
GANEA DOINA,
DELGADO MARIO
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb06954.x
Subject(s) - vasoactive intestinal peptide , receptor , chemistry , microbiology and biotechnology , signal transduction , creb , cytokine , tumor necrosis factor alpha , transcription factor , neuropeptide , endocrinology , biology , biochemistry , immunology , gene
A bstract : VIP and PACAP modulate the function of inflammatory cells through specific receptors. VIP/PACAP inhibit the production of TNFα, 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 TNFα, IL‐10, IL‐12, and NO are mostly mediated through the constitutively expressed VPAC 1 receptor, although the inducible expressed VPAC 2 may also participate. VIP/PACAP binding to VPAC 1 induces both a cAMP‐dependent and a cAMP‐independent pathways that regulate cytokine and NO production at the transcriptional level. VIP/PACAP inhibit TNFα 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 IkBα 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.