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* Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695;
Department of Medicine and Pharmacology and Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27510;
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan;
Morphogenesis and Intracellular Signaling, Unité Mixte de Recherche 144, Institut Curie-Centre National de la Recherche Scientifique, Paris, France;
¶ Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, Japan; and
|| Solution Oriented Research for Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan
Recent studies have revealed that TAK1 kinase is an essential intermediate in several innate immune signaling pathways. In this study, we investigated the role of TAK1 signaling in maintaining intestinal homeostasis by generating enterocyte-specific constitutive and inducible gene-deleted TAK1 mice. We found that enterocyte-specific constitutive TAK1-deleted mice spontaneously developed intestinal inflammation as observed by histological analysis and enhanced expression of IL-1β, MIP-2, and IL-6 around the time of birth, which was accompanied by significant enterocyte apoptosis. When TAK1 was deleted in the intestinal epithelium of 4-wk-old mice using an inducible knockout system, enterocytes underwent apoptosis and intestinal inflammation developed within 2–3 days following the initiation of gene deletion. We found that enterocyte apoptosis and intestinal inflammation were strongly attenuated when enterocyte-specific constitutive TAK1-deleted mice were crossed to TNF receptor 1–/– mice. However, these mice later (>14 days) developed ileitis and colitis. Thus, TAK1 signaling in enterocytes is essential for preventing TNF-dependent epithelium apoptosis and the TNF-independent development of ileitis and colitis. We propose that aberration in TAK1 signaling might disrupt intestinal homeostasis and favor the development of inflammatory disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from Association pour la Recherche contre le Cancer 3148 and Institut National du Cancer PL 043 to S.R., from National Institutes of Health (DK47700) to C.J., and from Crohn’s and Colitis Foundation of America and from National Institutes of Health (GM068812) to J.N.-T.
2 Address correspondence and reprint requests to Dr. Jun Ninomiya-Tsuji, Department of Environmental and Molecular Toxicology, North Carolina State University, Campus Box 7633, Raleigh, NC 27695. E-mail address: Jun_Tsuji{at}ncsu.edu
3 Abbreviations used in this paper: TAK1, TGF-β-activated kinase 1; DKO, double knockout; E, embryonic day; IKK, I
B kinase; P, postnatal day.
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