IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer.
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.
Grivennikov
Sergei
S
Laboratory of Gene Regulation and Signal Transduction, UCSD School of Medicine, University of California San Diego, La Jolla, CA 92093-0723, USA.
Karin
Eliad
E
Terzic
Janos
J
Mucida
Daniel
D
Yu
Guann-Yi
GY
Vallabhapurapu
Sivakumar
S
Scheller
Jürgen
J
Rose-John
Stefan
S
Cheroutre
Hilde
H
Eckmann
Lars
L
Karin
Michael
M
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
D015850:Interleukin-6; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha