Receptors and transcriptional factors involved in the anti-inflammatory activity of VIP and PACAP.

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.

05001000'02'04'06'08'10'12'14'16
Citations per Year

4,798 Citations

Semantic Scholar estimates that this publication has 4,798 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Leceta2000ReceptorsAT, title={Receptors and transcriptional factors involved in the anti-inflammatory activity of VIP and PACAP.}, author={Javier Leceta and Rosa P{\'e}rez Gomariz and Carmen Mart{\'i}nez and Catalina Abad and Doina Ganea and Mario Delgado}, journal={Annals of the New York Academy of Sciences}, year={2000}, volume={921}, pages={92-102} }