Introduction
Inflammatory bowel disease (IBD) is a chronic gut inflammatory disorder, and the dysfunction of intestinal epithelial barrier 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 lung1). However, the physiological role of SLPI in the intestine is largely unknown. Daikenchuto is one of the most frequently prescribed Japanese traditional herbal medicine for various digestive disorders. Although several animal studies have revealed that Daikenchuto exerts anti-inflammatory effects, the detailed molecular mechanism remains unclear2).
Aims & Methods
We aimed to clarify the role of SLPI in the pathogenesis of IBD using murine colitis model, and investigated the protective effect of Daikenchuto against colitis through the induction of SLPI. Using SLPI-deficient mice, pathological features of dextran sulfate sodium (DSS)-induced colitis, intestinal epithelial barrier function and neutrophil elastase (NE) activities were analyzed. To investigate a therapeutic effect, recombinant SLPI, protease inhibitor SSR69071 or Daikenchuto was administered to DSS-induced colitis model.
Results
We found that SLPI was induced in a lipopolysaccharides-treated colon carcinoma cell line in vitro and in the colon of DSS-treated mice in vivo. When SLPI-deficient mice were administered DSS to induce colitis, severe inflammation was sustained compared to wild-type mice. The colonic mucosa of SLPI-deficient mice showed more severe inflammation with neutrophil infiltration and higher levels of proinflammatory cytokines compared to control mice. Moreover, NE activity in SLPI-deficient mice was increased and intestinal epithelial barrier function was severely impaired in the colon. Importantly, we demonstrated that DSS-induced colitis was ameliorated by the administration of protease inhibitor SSR69071 and recombinant SLPI. In addition, we found that the expression of SLPI in the colon was significantly increased in Daikenchuto-treated mice, and DSS-induced colitis was attenuated by the administration of Daikenchuto.
Conclusion
These results suggest that the protease inhibitory activity of SLPI protects from colitis by preventing intestinal epithelial barrier 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. Furthermore, we showed that Daikenchuto exerts anti-inflammatory effect due, at least in part, to induction of SLPI in the colon.
References
1) Ashcroft GS, Lei K, Jin W, Longenecker G, Kulkarni AB, Greenwell-Wild T, Hale-Donze H, McGrady G, Song XY, Wahl SM. Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing. Nat Med. 2000 Oct;6(10):1147-53.
2) Shi Z, Takeuchi T, Nakanishi Y, Kato T, Beck K, Nagata R, Kageyama T, Ito A, Ohno H, Satoh-Takayama N. A Japanese Herbal Formula, Daikenchuto, Alleviates Experimental Colitis by Reshaping Microbial Profiles and Enhancing Group 3 Innate Lymphoid Cells. Front Immunol. 2022 Jun 2;13:903459.
Disclosure
This study received funding from Tsumura & Co.
