S1634 Inadequate Unfolded Protein Response As a Mechanism for Acute Colitis in Mbtps1 Mutant Mice

Abstract

Background: Although various environmental factors have been proposed to contribute to the enhanced risk of inflammatory bowel diseases (IBD), the role of stress in the pathogenesis of IBD has not been clearly elucidated. Previous studies reported the effect of exposure to restraint or cold stress on intestinal inflammation, however, the influence of psychological stress has not been well understood. Interleukin-18 (IL-18) was reported as IFN-γ inducing factor at first but has been found to have multiple biological activities. IL-18 is increased in response to ACTH in adrenal gland. It has been reported that IL-18 was elevated by immobilization stress in mice and that IL-6 induction by stress occurred in IL-18 dependent manner. In this study we investigated the effect of psychological stress on colonic inflammation and the change of cytokine expression in adrenal gland and colon. We also examined whether IL-18 mediates this process by using IL-18 knockout (KO) mice. Methods: Colitis was induced in eight-week-old male C57/BL6 mice and IL-18 KO mice by exposure to 3% dextran sulfate sodium (DSS) for 7 days. Some mice were given psychological stress for 2 hours a day for following 5 days of drug free period using the communication box method. In the communication box psychological stress was induced by showing other mice in the adjacent cells getting electrical foot shock intermittently. Mice were weighed everyday. On day 12 mice were sacrificed. The length of colon and the grade of histological damage of colitis were determined. The expression of inflammatory cytokines and adhesion molecules in the colon were analyzed by RT-PCR. The expression of IL-18 in the adrenal gland was analyzed as well. Results: DSS treatment significantly decreased body weight and colonic length. The addition of psychological stress resulted in less body weight, shorter colonic length, and further inflammation than DSS treatment alone. Stress increased the expression levels of inflammatory cytokines and adhesion molecules in the colon such as TNF-α, IL6, IL-18, IL-23a, MadCAM-1, and ICAM-1 compared to DSS treatment alone. In adrenal glands, stress or DSS treatment alone increased the expression level of IL-18, but it was further increased by combination. In IL-18 KO mice without psychological stress the degree of DSS colitis was not different from that of wild type mice. However the induction of stress did not aggravate colitis in IL-18 KO mice without further increase of proinflammatory cytokines expression. Conclusion: Psychological stress exacerbates colitis and IL-18 is suggested to mediate this process through the increase of proinflammatory cytokines.