Apoptosis signal-regulating kinase 1 regulates colitis and colitis-associated tumorigenesis by the innate immune responses.
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.
Hayakawa
Yoku
Y
Department of Gastroenterology, University of Tokyo, Tokyo 113-8655, Japan.
Hirata
Yoshihiro
Y
Nakagawa
Hayato
H
Sakamoto
Kei
K
Hikiba
Yohko
Y
Otsuka
Motoyuki
M
Ijichi
Hideaki
H
Ikenoue
Tsuneo
T
Tateishi
Keisuke
K
Akanuma
Masao
M
Ogura
Keiji
K
Yoshida
Haruhiko
H
Ichijo
Hidenori
H
Omata
Masao
M
Maeda
Shin
S
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
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