T1778 Reciprocal Modulation of Smooth Muscle Cell Contractility in TH1 and Th2 Dominant Environments Using Murine Model of Early Post Inflammatory Gut Dysfunction

Background & Aim: In the enteric-infection-induced model of inflammation, Th1 and Th2 cytokines have opposing effect on intestinal muscle function and 5-HT signaling (Motomura et al. Gut 2008; Gastroenterology 128;Suppl A 626,2005), but the role of Th1 and Th2 dominant environments for non-infective post-inflammatory (PI) gut dysfunction remains to be determined. Here we investigated the mechanism for gut dysfunction that persists after acute inflammation in Th1 and Th2 dominant environments utilizing mouse model of T cell-induced enteropathy. Methods: BALB/c (Th2 dominant response) and AKR (Th1 dominant response) mice were treated with an anti-CD3 antibody (100 μg), and sacrificed at days 0, 1, 3, 7, and 14 post-treatment to investigate the histological changes, longitudinal smooth muscle cell contraction, various cytokines (Th1, Th2, Th17 cytokines), chemokines, and mediators mRNA /protein expressions and 5-HT-expressing enterochromaffin (EC) cells numbers in the small intestine. Results: In BALB/c mice small intestinal tissue damage was observed from 24 hours after the anti-CD3 antibody injection, but had resolved by day 5. Carbachol-induced smooth muscle cell contractility was significantly increased (p<0.05) from 4 hours after injection, and this muscle hypercontractility was evident (p<0.05) in the early PI phase (at day 7). Th2 cytokines (IL-4, IL-13) were significantly increased (p<0.05) from 4 hours to day 7 in the small intestine. EC cells in the intestine were significantly increased from day 1 to day 7 (p<0.05). On the contrary in AKR mice carbachol-induced smooth muscle cell contractility was significantly decreased from 4 hours after injection (p<0.05), and this muscle hypocontractility was evident until day 14. Th1 cytokines (IFNγ) were increased from 4 hours to day 7 in the small intestine. Conclusions: Intestinal muscle dysfunction in the early PI phase is maintained at the smooth muscle cell level. Th1 and Th2 cytokines have opposing effect on intestinal muscle contraction via 5-HT signaling in the early PI phase in this model. The gut dysfunctions in the early PI phase are influenced by Th1 or Th2 cytokine predominance environments.