Role of tumor necrosis factor receptor 2 (TNFR2) in colonic epithelial hyperplasia and chronic intestinal inflammation in mice

Background & Aims: Tumor necrosis factor (TNF) induces multiple effects including cell proliferation and death by ligation with TNF receptor type II (TNFR2). We studied the role of TNFR2 in chronic inflammation-induced colonic epithelial alteration. Methods: TNFR2 expression in colonic epithelial cells (CECs) was assessed by ribonuclease protection assay (RPA) and immunohistochemistry (IHC) in patients with inflammatory bowel disease (IBD) and murine colitis models, TNFR2 expression was also analyzed using COLO205 cells. The role of TNFR2 in colonic epithelial homeostasis was examined by generating interleukin 6-deficient TCRalphaKO (alphaIL-6DKO) or TNFR2-deficient TCRalpha (alphaTNFR2DKO) mice. Results: TNFR2 expression was up-regulated in CEC in both human ulcerative colitis and Crohn's disease. In vitro studies showed that TNFR2 expression was up-regulated by a cooperative effect of key proinflammatory cytokines. By RPA, the increased expression of TNFR2 was detectable in TCRalphaKO mice with colitis compared with TCRalphaKO mice without colitis or wild-type mice. In alphaIL-6DKO mice, TNFR2 expression, proliferation, and nuclear factor kappa B activation of CECs were markedly reduced compared with TCRalphaKO mice. alphaTNFR2 mice also showed significantly less colonic epithelial proliferation compared with TCRalphaKO mice. Conclusions: Expression of TNFR2 is consistently increased on CECs in both murine colitis models as well as patients with IBD. TNFR2 may play an important role in colonic inflammation-associated alteration in the intestinal epithelium.