Apoptosis Signal-Regulating Kinase 1 Regulates Colitis and Colitis-Associated Tumorigenesis by the Innate Immune Responses

Background & Aims

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.

Keywords: ASK1, Innate Immunity, Colitis, Colitis-Associated Cancer

Abbreviations used in this paper: AOM, azoxymethane, ASK1, apoptosis signal-regulating kinase, BMDM, bone marrow–derived macrophage, CAC, colitis-associated cancer, DSS, dextran sulfate sodium, ELISA, enzyme-linked immunoabsorbent assay, IBD, inflammatory bowel diseases, IL, interleukin, JNK, c-Jun NH2-terminal kinase, LPS, lipopolysaccharide, MAPK, mitogen-activated protein kinase, MPO, myeloperoxidase, NF-κB, nuclear factor-κB, PCR, polymerase chain reaction, ROS, reactive oxygen species, siRNA, small interfering RNA, TLR4, Toll-like receptor 4, TNF-α, tumor necrosis factor-α, TRAF6, tumor necrosis factor receptor-associated factor 6, TUNEL, transferase-mediated dUTP nick end labeling, WT, wild-type.