Apoptosis Signal-Regulating Kinase 1 Regulates Colitis and Colitis-Associated Tumorigenesis by the Innate Immune Responses
Received 12 June 2009; accepted 12 November 2009. published online 19 November 2009. Uncorrected Proof
Background & Aims
Mitogen-activated protein kinase (MAPK) signaling pathways regulate multiple cellular functions and are implicated in the pathogenesis of inflammatory bowel disease and colitis-associated cancer (CAC). Apoptosis signal-regulating kinase 1 (ASK1) is a (MAPK) kinase kinase; little is known about the role of ASK1 in colonic disease. We assessed the involvement of ASK1 in the development of intestinal inflammation and CAC.
Methods
Dextran sodium sulfate (DSS) or Citrobacter rodentium were used to induce colitis in wild-type (WT) and ASK1 knock-out (ASK1−/−) mice; CAC was induced by azoxymethane injection followed by repeated intake of DSS by the mice. Primary macrophages were isolated from WT and ASK1−/− mice and used to investigate the involvement of ASK1 in innate immune responses. Bone marrow chimeric mice were used to study the contribution of myeloid cells to colitis activity.
Results
ASK1 deficiency increased susceptibility to colonic inflammation in both models of colitis. In vitro, ASK1−/− macrophages were impaired in their ability to kill bacteria and had increased susceptibility to bacterial-induced apoptosis, because p38 was inactivated. Expression of antiapoptotic genes was greatly reduced in ASK1−/− macrophages. WT mice given transplants of ASK1−/− mouse-derived bone marrow cells developed more severe DSS-induced colitis than mice with WT-derived bone marrow cells. In the CAC model, ASK1−/− mice developed more numerous and larger tumors than WT mice through increased colonic inflammation.
Conclusions
ASK1 controls the development of intestinal inflammation and CAC through the regulation of innate immunity.
⁎Department of Gastroenterology, University of Tokyo, Tokyo, Japan
‡Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan
§Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan
Reprint requests Address requests for reprints to: Shin Maeda, Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655. fax: (81) 3-3814-0021
Conflicts of interest The authors disclose no conflicts.
Author contributions were as follows: Y. Hayakawa provided the study concept and design, acquired data, analyzed and interpreted data, and drafted the manuscript. Y. Hirata provided study concept and design, analyzed and interpreted data, and drafted the manuscript. H.N. provided study concept and design, acquired data, and analyzed and interpreted data. K.S., M. Otsuka, H. Ijichi, T.I., K.T., M.A., and K.O. provided study concept and design and analyzed and interpreted data. Y.H. analyzed and interpreted data and provided technical or material support. H.Y. provided study concept and design, analyzed and interpreted of data, and analyzed statistics. H. Ichijo provided study concept and design, analyzed and interpreted data, and provided technical or material support. M. Omata provided study concept and design, obtained funding, supervised the study. S.M. provided study concept and design, analyzed and interpreted data, drafted the manuscript, critically revised the manuscript for important intellectual content, obtained funding, and supervised the study.
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Funding S.M. and K.O. were supported by grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (19390205).
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