Tu1940 Cigarette Smoke Improves Selectively Colon and Not Small Bowel Inflammation Through NKT Cell Activation

INTRODUCTION Epidemiological studies strongly linked cigarette smoking and inflammatory bowel diseases (IBD). Smoking protects against ulcerative colitis but increases the risk of developing Crohn's disease. The mechanisms sustaining the dual effects of cigarette smoke (CS) in IBD remain unknown. AIM To compare the effect of CS on small bowel and colon inflammation in mice and to characterize the mechanisms of action at cellular and molecular levels. METHODS C57BL/6 mice and NKT deficient mice (Jα18KO and CD1dKO) were exposed during 3 weeks to CS of 5 cigarettes/days using the InExpose® exposure system (Scireq Inc). Colitis abd ileitis were induced respectively by administration of 2.5 % DSS in drinking water or indomethacin (100mg/kg s.c.). Intestinal inflammation was assessed by clinical scores, quantification of the recruitment of cells in the gut by flow cytometry analysis and evaluation of intestinal cytokines by quantitative RT-PCR and ELISA. RESULTS In wild-type mice, CS exposure improved selectively DSS-induced colitis and not indomethacininduced iletitis, leading to an improvement of body weight loss (n=30; p<0.0001), clinical score (p=0.01) and weight/length colon ratio (p<0.0001)). This colonic improvement was associated with a significant decrease in colonic TNF (p=0.0169), IFNγ (p<0.0001) and IL22 (p=0.0016) mRNA expression together with an increased expression of IL-10 mRNA (p= 0.0035). CS induced a recruitment of activated Natural Killer T cells (CD45+ TCRβ+ CD1d tetramer+) in the colon without any modification of neutrophil infiltration (CD45+ CD11cLy6G+) and activation (MPO activity). Demonstration of the roles of NKT cells in CSinduced colitis improvement was performed using 2 different strains of NKT deficient mice. Indeed, in Jα18KO and CD1dKO animals, CS exposure failed to induce significant regulation of DSS-induced colitis both at the clinical and molecular levels. Restoration of the CS regulation on DSS-induced colitis was obtained in Jα18KO animals after adoptive transfer of WT NKT cells exposed to CS. CONCLUSION The regulatory role of CS on intestinal inflammation is more pronounced in the colon than the small bowel in mice. This protective effect is mediated at least in part through the colonic recruitment and activation of NKT cells.