Abstract
Crohn’s disease, a chronic and recurrent gastrointestinal disease, frequently causes intestinal fibrosis. Transient receptor potential melastatin 2 (TRPM2) belonging to TRP channel family is activated by reactive oxygen species. This study investigated the role of TRPM2 in acute colitis and chronic colitis-associated fibrosis progression. Acute colitis and chronic colitis-associated fibrosis were induced in TRPM2-deficient (KO) and wild-type (WT) mice through single and repeated intrarectal injections of trinitrobenzene sulfonic acid (TNBS). Bone marrow-derived macrophages (BMDMs) were created by M-CSF stimulation. In WT, a single TNBS injection induced acute colitis and upregulated inflammatory cytokines/chemokines, Th1 and Th17-related cytokines, and their transcription factors. In contrast, repeated TNBS injections induced chronic colitis-associated fibrosis and upregulation of fibrogenic factors, Th2-related cytokines, and its transcription factor. However, these increases were considerably suppressed in KO. Treating BMDMs with H2O2 increased inflammatory, Th1 and Th17-related cytokines expression, and JNK and ERK phosphorylation, but these responses were significantly less in KO than those in WT. These finding suggest that TRPM2 contributes to acute colitis progression via Th1/Th17-mediated immune responses. Furthermore, TRPM2 may be directly involved in colitis-associated fibrosis induction, likely due to the regulation of Th2/TGF-β1-mediated fibrogenesis in addition to a consequence of acute colitis progression.
