Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis.
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-1beta, 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.
Kajino-Sakamoto
Rie
R
Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695, USA.
Inagaki
Maiko
M
Lippert
Elisabeth
E
Akira
Shizuo
S
Robine
Sylvie
S
Matsumoto
Kunihiro
K
Jobin
Christian
C
Ninomiya-Tsuji
Jun
J
D000818:Animals; D017209:Apoptosis; D003092:Colitis / Q000276:immunology* / Q000378:metabolism; D020895:Enterocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007079:Ileitis / Q000276:immunology* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D020930:MAP Kinase Kinase Kinases; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7