Influence of Interleukin-13 in 5-HT Synthesis and Severity of Experimental Colitis

Abstract

BACKGROUND: Mucosal inflammation in conditions ranging from infective acute enteritis or colitis to inflammatory bowel disease is accompanied by alteration in serotonin (5hydroxytryptamine, 5-HT) content in the gut. In our previous studies, we have shown that 5-HT plays an important role in the pathogenesis of experimental colitis. Dendritic cells (DC) are important innate immune cells and play a key role in the activation of the immune response and generation of gut inflammation. DCs express the 5-HT7 receptor, and we have recently demonstrated that 5-HT plays an important role in DC activation in relation to gut inflammation. In this study, we have evaluated the effect of inhibiting 5-HT signaling by using a 5-HT7 receptor antagonist or 5-HT7 receptor knockout mice in experimental colitis. METHODS: Mice (C57BL/6) were treated with selective 5-HT7 receptor antagonist SB266970 (40mg/kg, ip) or vehicle (saline) starting one day prior to administration of 5% dextran sulfate sodium (DSS) in drinking water and were sacrificed on day 5 post-DSS to assess the extent of colitis, myeloperoxidase (MPO) activity and pro-inflammatory cytokines. Colitis was also induced in 5-HT7 receptor deficient mice on C57BL/6 background (5HT7KO) and wild type mice either by 5% DSS or intrarectal administration of dinitrobenzene sulfonic acid (DNBS, 5mg/mouse) and were sacrificed on day 5 post-DSS and day 3 postDNBS to assess the extent of colitis, MPO activity and pro-inflammatory cytokines. RESULTS: Inhibition of 5-HT signaling by blocking 5-HT7 receptor function with a 5-HT7 antagonist ameliorated DSS-induced colitis. Compared to saline treated mice, we observed significantly lower macroscopic (4.0±0.28 vs. 2.6±0.43) and histological damage scores (4.8±0.59 vs. 2.4±0.54) in antagonist treated mice on day 5 post-DSS. This was associated with downregulation of MPO activity (16.9±0.88 vs. 12.32±1.21, P<0.05) and lower production of IL-1β, TNF-α and IL-6 (P<0.05) post-DSS. There were also significantly lower histological scores, MPO and pro-inflammatory cytokine levels in 5-HT7KOmice as compared to controls post-DSS. DCs isolated from 5-HT7KO mice post-DSS produced lower levels of IL-12 and IL-1β when stimulated with LPS as compared to wild-type mice (P<0.05). We also observed significant reduction in severity of colitis in 5-HT7KO mice following induction of DNBScolitis. CONCLUSION: These results demonstrate that disruption of 5-HT7 receptor function reduces the severity of gut inflammation and identifies a key role of 5-HT7 receptor mediated signaling in the pathogenesis of experimental colitis. These observations provide us with novel information on the role of the 5-HT7 receptor in gut inflammation and highlight the potential benefit of targeting this receptor to alleviate disease severity in intestinal inflammatory conditions including inflammatory bowel disease.