5-HT can regulate inflammation by acting on signalling pathways in inflammation,

production of inflammatory mediators from immune cells and promoting interaction between innate and adaptive immune response. Recently we have investigated the role of 5-HT in colonic inflammation in two different models of colitis (DSS and DNBS) using tryptophan hydroxylase1-deficient (TPH1−/−), mice, which have significantly reduced amounts of 5-HT in gut, and in mice treated with 5-HT synthesis inhibitor parachlorophenylalanine (PCPA) [37]. Delayed onset and decreased severity of colitis were observed in TPH1−/− mice compared to wild-type mice and in PCPA-treated mice after induction of colitis by DSS. This was associated with down-regulation of macrophage infiltration and production of proinflammatory cytokines. Restoration of 5-HT amounts in TPH1−/− mice by administration

of 5-HT precursor 5-HTP enhanced the severity MG-132 supplier of DSS-induced colitis. We also observed a significant reduction in severity of colitis in TPH1−/− mice after induction of DNBS-colitis. Our data complement the recent study published by Bischoff et al., which demonstrated that TNBS-induced colitis is increased in severity when coupled with the 5-HT-enhancing effects by knock-out of SERT gene [51]. Recent studies from our RAD001 purchase laboratory also demonstrate that dendritic cells from TPH1−/− mice in DSS-colitis produced reduced IL-12 compared to TPH1+/+ mice and

stimulation with 5-HT restored IL-12 production from the dendritic cells from naive TPH1−/− mice [52]. Taken together, these studies show a critical role of 5-HT in the pathogenesis of inflammation Sunitinib in gut by influencing proinflammatory cytokine production in experimental colitis and provide new insights into the mechanisms of gut inflammation. In a wider context, a beneficial effect with treatment with 5-HT receptor antagonist has been shown in both clinical and experimental arthritis [53], implicating a role of 5-HT in the pathogenesis of non-GI-inflammation in addition to GI inflammation. As presented above, 5-HT is present throughout the GI tract and plays an important role in the regulation of the development of gut inflammation and various physiological activities in the gut. In addition to 5-HT, enteric endocrine cells produce the granins family [40] of biologically active products, which include Cgs A/B [54] and secretogranin, which can also contribute to various GI functions including immune modulation and inflammation. The granin family consists of single-polypeptide chains of 185–657 amino acid residues. The numerous pairs of basic amino acids indicate a potential site for cleavage by prohormone convertases PC1/3 and PC2 in the secretory granules [55]. More than 10 different proteolytic sites have been identified in the CgA.