Protease inhibitory activity of secretory leukocyte protease inhibitor ameliorates murine experimental colitis by protecting the intestinal epithelial barrier

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder in the intestine, and the dysfunction of intestinal epithelial barrier (IEB) may trigger the onset of IBD. Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor that has been implicated in the tissue‐protective effect in the skin and lung. We found that SLPI was induced in lipopolysaccharides‐treated colon carcinoma cell line and in the colon of dextran sulfate sodium (DSS)‐treated mice. SLPI‐deficient mice were administered DSS to induce colitis and sustained severe inflammation compared with wild‐type mice. The colonic mucosa of SLPI‐deficient mice showed more severe inflammation with neutrophil infiltration and higher levels of proinflammatory cytokines compared with control mice. Moreover, neutrophil elastase (NE) activity in SLPI‐deficient mice was increased and IEB function was severely impaired in the colon, accompanied with the increased number of apoptotic cells. Importantly, we demonstrated that DSS‐induced colitis was ameliorated by administration of protease inhibitor SSR69071 and recombinant SLPI. These results suggest that the protease inhibitory activity of SLPI protects from colitis by preventing IEB dysfunction caused by excessive NE activity, which provides insight into the novel function of SLPI in the regulation of gut homeostasis and therapeutic approaches for IBD. We have revealed that SLPI is induced by inflammatory stimuli in the intestine and exerts a protective effect against colitis by protecting the intestinal epithelial barrier. Importantly, administration of recombinant SLPI and protease inhibitor SSR69071 could ameliorate DSS‐induced colitis. Hence, we have demonstrated a pivotal role for SLPI in regulating intestinal inflammation, as well as provided insight into a novel therapeutic target for treatment of IBD.