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Am J Physiol Gastrointest Liver Physiol 296: G850-G859, 2009. First published January 29, 2009; doi:10.1152/ajpgi.00071.2008
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INFLAMMATION/IMMUNITY/MEDIATORS

Signaling pathway via TNF-{alpha}/NF-{kappa}B in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis

Michio Onizawa,1,* Takashi Nagaishi,1,* Takanori Kanai,1 Ken-ichi Nagano,2 Shigeru Oshima,1 Yasuhiro Nemoto,1 Atsushi Yoshioka,1 Teruji Totsuka,1 Ryuichi Okamoto,1 Tetsuya Nakamura,1 Naoya Sakamoto,1 Kiichiro Tsuchiya,1 Kazuhiro Aoki,2 Keiichi Ohya,2 Hideo Yagita,3 and Mamoru Watanabe1

1Department of Gastroenterology and Hepatology, Graduate School of Medicine and 2Section of Pharmacology, Department of Hard Tissue Engineering, Tokyo Medical and Dental University, Tokyo; and 3Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan

Submitted 13 February 2008 ; accepted in final form 11 January 2009

Treatment with anti-TNF-{alpha} MAb has been accepted as a successful maintenance therapy for patients with inflammatory bowel diseases (IBD). Moreover, it has been recently reported that blockade of TNF receptor (TNFR) 1 signaling in infiltrating hematopoietic cells may prevent the development of colitis-associated cancer (CAC). However, it remains unclear whether the TNF-{alpha} signaling in epithelial cells is involved in the development of CAC. To investigate this, we studied the effects of anti-TNF-{alpha} MAb in an animal model of CAC by administration of azoxymethane (AOM) followed by sequential dextran sodium sulfate (DSS) ingestion. We observed that the NF-{kappa}B pathway is activated in colonic epithelia from DSS-administered mice in association with upregulation of TNFR2 rather than TNFR1. Immunoblot analysis also revealed that the TNFR2 upregulation accompanied by the NF-{kappa}B activation is further complicated in CAC tissues induced in AOM/DSS-administered mice compared with the nontumor area. Such NF-{kappa}B activity in the epithelial cells is significantly suppressed by the treatment of MP6-XT22, an anti-TNF-{alpha} MAb. Despite inability to reduce the severity of colitis, sequential administration of MP6-XT22 reduced the numbers and size of tumors in association with the NF-{kappa}B inactivation. Taken together, present studies suggest that the TNFR2 signaling in intestinal epithelial cells may be directly involved in the development of CAC with persistent colitis and imply that the maintenance therapy with anti-TNF-{alpha} MAb may prevent the development of CAC in patients with long-standing IBD.

tumor necrosis factor-{alpha}; colitis-associated cancer; intestinal epithelial cells; carcinogenesis; TNFR2


Address for reprint requests and other correspondence: t. Kanai, Dept. of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental Univ., 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan (e-mail: taka.gast{at}tmd.ac.jp)






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