title: IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer.
abstract: Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Proinflammatory cytokines have been suggested to regulate preneoplastic growth during CAC tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-kappaB-regulated cytokine that acts on epithelial and immune cells. Using genetic tools, we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor-initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and premalignant intestinal epithelial cells (IECs) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by the transcription factor Stat3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-kappaB-IL-6-Stat3 cascade is an important regulator of the proliferation and survival of tumor-initiating IECs.
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, UCSD School of Medicine, University of California San Diego, La Jolla, CA 92093-0723, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Grivennikov
authors.forename: Eliad
authors.initials: E
authors.lastname: Karin
authors.forename: Janos
authors.initials: J
authors.lastname: Terzic
authors.forename: Daniel
authors.initials: D
authors.lastname: Mucida
authors.forename: Guann-Yi
authors.initials: GY
authors.lastname: Yu
authors.forename: Sivakumar
authors.initials: S
authors.lastname: Vallabhapurapu
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Hilde
authors.initials: H
authors.lastname: Cheroutre
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology*; D003093:Colitis, Ulcerative / Q000150:complications* / Q000276:immunology / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000166:cytology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000209:etiology / Q000276:immunology / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha