Journal
JOURNAL OF IMMUNOLOGY
Volume 181, Issue 2, Pages 1143-1152Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.181.2.1143
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Funding
- NIDDK NIH HHS [DK47700, R01 DK047700, R56 DK047700] Funding Source: Medline
- NIGMS NIH HHS [GM068812, R01 GM068812, R01 GM068812-02, R01 GM068812-03] Funding Source: Medline
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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-1 beta, 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.
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