Increased susceptibility to colitis in the Vasoactive Intestinal Peptide receptor type 2 (VPAC2) mouse : A negative role for VPAC1 receptor in the induction of intestinal inflammation (50.44)

Abstract

Abstract Vasoactive intestinal peptide (VIP) is a prominent neuropeptide with effects on many immune functions which are transduced by VIP G-protein-coupled receptors type 1 (VPAC1) and type 2 (VPAC2) on immune cells. Previous studies have shown that VIP reduces clinical symptoms and inflammation in mouse models of human immune-based diseases such as rheumatoid arthritis, Crohn's Disease, septic shock and multiple sclerosis. We recently demonstrated that VPAC2 knockout (KO) CD4 T cells in the presence of VIP and TGF-b develop into Th17 cells in a cAMP-Protein Kinase A dependent manner. Here we show that increased IL-17 induction in VPAC2-KO CD4 cells is accompanied by a reduced conversion of CD4 T cells into FoxP3+ regulatory T cells. To determine if VPACs play a role in the inflammatory bowel disease (IBD), VPAC2-KO mice were subjected to dextran sulfate sodium (DSS) in drinking water. Compared to wild type (WT), VPAC2-KO mice exhibited rapid and more severe clinical symptoms of colitis and had significantly higher colonic inflammation and increased inflammatory cytokines in colon. Severe colitis in VPAC2-KO mice was ameliorated in the presence of PKA inhibitors. Moreover, VPAC1-KO mice were resistant to the development of DSS-induced colitis. The results demonstrate a new role for VPAC1 which is responsible for increased inflammation in IBD and may provide a new therapeutic target.