IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer
Open accessAbstract
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.
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IL-6 binds to gp130 on target cells to activate STAT3 in tumour cells and tumour-associated inflammatory cells.
“IL-6 binds to gp130 on target cells to activate the signal transducer and activator of transcription 3 [STAT3] in tumour cells and tumour-associated inflammatory cells 12, 15.”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [12]
The Introduction (page not available) says IL-6 binds IL-6R, which interacts with gp130 to activate downstream STAT3; it does not say IL-6 binds gp130 directly. The Significance section (page not available) identifies STAT3 as mediating IL-6’s effects on pre-malignant intestinal epithelial cells, but describes inflammatory myeloid cells as IL-6 producers, not as cells in which IL-6 activates STAT3. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIL-6 has been previously identified as a key cytokine that directly induces tumour growth in CRC via STAT3 activation in IECs.
“IL-6 has been previously identified as a key cytokine that directly induces tumuor growth in CRC via STAT3 activation in IECs.12,15,46,47.”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [12]
The Introduction and Discussion report that IL-6 promotes tumor growth through STAT3 activation in intestinal epithelial cells. The experiments establish this in a mouse model of colitis-associated cancer (CAC), not colorectal cancer (CRC) generally, so the claim extends the finding beyond the studied setting. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSTAT3 is involved in inflammation-associated carcinogenesis, suppression of the antitumor immune response, and maintenance of cancer stem cells.
“STAT3 is also involved in inflammation-associated carcinogenesis, suppression of the antitumor immune response, and maintenance of cancer stem cells.”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [94]
The Discussion (page not provided) reports that STAT3 ablation in intestinal epithelial cells reduced tumor formation and growth in a mouse model of colitis-associated cancer, supporting its role in inflammation-associated carcinogenesis. The passages do not establish that STAT3 suppresses the antitumor immune response or maintains cancer stem cells; searches for those points found no supporting passage. (LLM, conf=0.86)
Experimental — accuracy not yet measuredIL-6R evokes a myriad of responses, including metabolic actions, through STAT3.
“IL-6R evokes a myriad of responses, including metabolic actions, through STAT3.31,32,33,34”
From Dynamic IL-6R/STAT3 signaling leads to heterogeneity of metabolic phenotype in pancreatic ductal adenocarcinoma cells (2024) · cites this paper as [33]
The Discussion (page unavailable) says IL-6 binding to its gp130-associated receptor activates the JAK1/2–STAT3 pathway and identifies STAT3 as a critical effector in colitis-associated cancer. It discusses effects on intestinal epithelial cell survival and proliferation, but does not establish the claimed metabolic actions through STAT3. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIL-6 is a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6-STAT3 pathway.
“IL-6 is also a key factor in inflammation, autoimmunity and cancer, with its effect mainly exerted through the IL-6–signal transducer and activator of transcription 3 (STAT3) pathway (18–26, 61–65).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [18]
The Introduction describes IL-6 as important in chronic inflammation, T-cell-dependent autoimmune disorders and cancer. The Discussion identifies STAT3 as a major IL-6 effector in colitis-associated cancer, but also lists two other IL-6 signaling pathways. It does not establish that IL-6 acts mainly through STAT3 across all three settings. (LLM, conf=0.85)
Experimental — accuracy not yet measured
The IL-6/JAK/STAT3 signalling pathway plays an important role in human malignancies such as CRC.
“The IL-6/JAK/STAT3 signalling pathway plays an important role in human malignancies such as CRC.12,15,46,48,49”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [12]
IL-6 and STAT3 are required for activated mutant EGFR-induced lung cancer and colitis-associated cancer.
“The requirement of IL-6 and STAT3 for activated mutant EGFR-induced lung cancer and colitis-associated cancer has also been demonstrated (18, 257).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [18]
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- Authors
- Grivennikov, S., Karin, E., Terzic, J., Mucida, D., Yu, G.-Y., Vallabhapurapu, S., Scheller, J., Rose-John, S., Cheroutre, H., Eckmann, L., & Karin, M.
- Affiliations
- University of California San Diego (US)
- La Jolla Institute for Immunology (US)
- Christian-Albrechts-Universität zu Kiel (DE)
- Corresponding author
- Karin, Michael
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 15
- Issue
- 2
- Pages
- 103-113
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC2667107
- OpenAlex
- W2082626794
- Cited by
- 2,155
- References
- 7
- Citations by year
- 2026: 90 · 2025: 77 · 2024: 111 · 2023: 108 · 2022: 115 · 2021: 138 · 2020: 128 · 2019: 140 · 2018: 139 · 2017: 139 · 2016: 135 · 2015: 153 · 2014: 128 · 2013: 162 · 2012: 124
- FWCI
- 64.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2118 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Cancer Society
- Crohn's and Colitis Foundation of America (1762)
- American Physicians Fellowship for Medicine in Israel
- Fulbright Association
- Deutsche Forschungsgemeinschaft (SFB415)
- National Institutes of Health
- EMBO
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Keywords
- interleukin-6, STAT3, colitis-associated colorectal cancer, inflammatory bowel disease, intestinal epithelial cells, apoptosis, cancer stem cells, NF-κB signaling, tumor promotion, cell proliferation
- MeSH terms
- Animals, Bone Marrow Cells, Cell Survival, Colitis, Ulcerative, Epithelial Cells, Gene Expression Regulation, Humans, Intestinal Mucosa, Mice, Inbred C57BL, Neoplasms, Tumor Necrosis Factor-alpha, Signal Transduction, Interleukin-6, NF-kappa B, Mice, Knockout, Cell Proliferation, STAT3 Transcription Factor, Mice
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