title: Apoptosis signal-regulating kinase 1 regulates colitis and colitis-associated tumorigenesis by the innate immune responses.
abstract: OBJECTIVE
  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 was 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.
authors.affiliation: Department of Gastroenterology, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hirata
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hikiba
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Otsuka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Ijichi
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Ikenoue
authors.forename: Keisuke
authors.initials: K
authors.lastname: Tateishi
authors.forename: Masao
authors.initials: M
authors.lastname: Akanuma
authors.forename: Keiji
authors.initials: K
authors.lastname: Ogura
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Yoshida
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001397:Azoxymethane; D016026:Bone Marrow Transplantation; D049109:Cell Proliferation; D002478:Cells, Cultured; D044082:Citrobacter rodentium; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D034622:RNA Interference; D012720:Severity of Illness Index; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016264:Dextran Sulfate; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; C482859:Map3k5 protein, mouse; D001397:Azoxymethane