title: Intestinal epithelial-derived TAK1 signaling is essential for cytoprotection against chemical-induced colitis.
abstract: BACKGROUND
  We have previously reported that intestinal epithelium-specific TAK1 deleted mice exhibit severe inflammation and mortality at postnatal day 1 due to TNF-induced epithelial cell death. Although deletion of TNF receptor 1 (TNFR1) can largely rescue those neonatal phenotypes, mice harboring double deletion of TNF receptor 1 (TNFR1) and intestinal epithelium-specific deletion of TAK1 (TNFR1KO/TAK1(IE)KO) still occasionally show increased inflammation. This indicates that TAK1 is important for TNF-independent regulation of intestinal integrity.
  
  
  RESULTS
  In this study, we investigated the TNF-independent role of TAK1 in the intestinal epithelium. Because the inflammatory conditions were sporadically developed in the double mutant TNFR1KO/TAK1(IE)KO mice, we hypothesize that epithelial TAK1 signaling is important for preventing stress-induced barrier dysfunction. To test this hypothesis, the TNFR1KO/TAK1(IE)KO mice were subjected to acute colitis by administration of dextran sulfate sodium (DSS). We found that loss of TAK1 significantly augments DSS-induced experimental colitis. DSS induced weight loss, intestinal damages and inflammatory markers in TNFR1KO/TAK1(IE)KO mice at higher levels compared to the TNFR1KO control mice. Apoptosis was strongly induced and epithelial cell proliferation was decreased in the TAK1-deficient intestinal epithelium upon DSS exposure. These suggest that epithelial-derived TAK1 signaling is important for cytoprotection and repair against injury. Finally, we showed that TAK1 is essential for interleukin 1- and bacterial components-induced expression of cytoprotective factors such as interleukin 6 and cycloxygenase 2.
  
  
  CONCLUSIONS
  Homeostatic cytokines and microbes-induced intestinal epithelial TAK1 signaling regulates cytoprotective factors and cell proliferation, which is pivotal for protecting the intestinal epithelium against injury.
authors.affiliation: Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina, United States of America.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Rie
authors.initials: R
authors.lastname: Kajino-Sakamoto
authors.forename: Emily
authors.initials: E
authors.lastname: Omori
authors.forename: Christian
authors.initials: C
authors.lastname: Jobin
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D003092:Colitis / Q000139:chemically induced / Q000209:etiology*; D051546:Cyclooxygenase 2; D016264:Dextran Sulfate; D015850:Interleukin-6; D007413:Intestinal Mucosa / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D015398:Signal Transduction; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D051546:Cyclooxygenase 2; D016264:Dextran Sulfate; D015850:Interleukin-6; D020930:MAP Kinase Kinase Kinases; D047888:Receptors, Tumor Necrosis Factor, Type I; D000099151:MAP Kinase Kinase Kinase 7; C506236:Tnfrsf1a protein, mouse