The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
Regulation of the IL-23 and IL-12 Balance by Stat3 Signaling in the Tumor Microenvironment
Open accessAbstract
SUMMARY Interactions between tumor and immune cells either enhance or inhibit cancer progression. We show here that Stat3 signaling within the tumor microenvironment induces a pro-carcinogenic cytokine, IL-23, while inhibiting a central anti-carcinogenic cytokine, IL-12, thereby shifting the balance of tumor immunity towards carcinogenesis. Stat3 induces expression of IL-23, which is mainly produced by tumor-associated macrophages, via direct transcriptional activation of the IL-23/p19 gene. Furthermore, Stat3 inhibits NF-κB/c-Rel-dependent IL-12/p35 gene expression in tumor-associated dendritic cells. Tumor-associated regulatory T cells (Treg) express IL-23 receptor (IL-23R) which activates Stat3 in this cell type, leading to upregulation of the Treg-specific transcription factor, Foxp3, and the immunosuppressive cytokine, IL-10. These results demonstrate that Stat3 promotes IL-23-mediated pro-carcinogenic immune responses while inhibiting IL-12-dependent anti-tumor immunity. SIGNIFICANCE Recent studies suggest that two related cytokines, IL- 23 and IL- 12, play opposite roles in carcinogenesis. However, the underlying mechanisms regulating the balance between these cytokines in the tumor microenvironment have not been elucidated. Mechanisms by which IL-23 promotes tumor immune evasion also remain to be explored. Our results reveal that Stat3 signaling in the tumor microenvironment regulates the IL-12/IL-23 balance and further, that IL- 23 enhances the immunosuppressive activity of regulatory T cells within the tumor microenvironment, in part via IL-23 receptor dependent Stat3 activation. Because Stat3 is a point of convergence for signaling pathways commonly activated in cancer, our data reveal a mechanism by which oncogenic pathways regulate the immune microenvironment to promote tumor development.
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Cites
IL-23 drives a pathogenic T cell population that induces autoimmune inflammation
Langrish, C. L., Chen, Y., Blumenschein, W. M., Mattson, J., Basham, B., Sedgwick, J. D., McClanahan, T., Kastelein, R. A., & Cua, D. J. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041257 · Cited by 4,099
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“Dying tumor cells have also been shown to stimulate DC IL-12 production (Apetoh et al., 2007).”
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The STATs of cancer — new molecular targets come of age
Yu, H., & Jove, R. (2004) · Nature Reviews Cancer · doi:10.1038/nrc1275 · Cited by 2,278
Self-citationDivergent Pro- and Antiinflammatory Roles for IL-23 and IL-12 in Joint Autoimmune Inflammation
Murphy, C. A., Langrish, C. L., Chen, Y., Blumenschein, W., McClanahan, T., Kastelein, R. A., Sedgwick, J. D., & Cua, D. J. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20030896 · Cited by 1,669
Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice
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IL-23 promotes tumour incidence and growth
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Sutmuller, R. P. M., van Duivenvoorde, L. M., van Elsas, A., Schumacher, T. N. M., Wildenberg, M. E., Allison, J. P., Toes, R. E. M., Offringa, R., & Melief, C. J. M. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.194.6.823 · Cited by 1,008
Cited by
Immunity, Inflammation, and Cancer
Grivennikov, S. I., Greten, F. R., & Karin, M. (2010) · Cell · doi:10.1016/j.cell.2010.01.025 · Cited by 10,755
STATs in cancer inflammation and immunity: a leading role for STAT3
Yu, H., Pardoll, D., & Jove, R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2734 · Cited by 4,383
Self-citationThe JAK/STAT signaling pathway: from bench to clinic
Hu, X., li, J., Fu, M., Zhao, X., & Wang, W. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00791-1 · Cited by 2,633
Wu, S., Rhee, K.-J., Albesiano, E., Rabizadeh, S., Wu, X., Yen, H.-R., Huso, D. L., Brancati, F. L., Wick, E., McAllister, F., et al. (2009) · Nature Medicine · doi:10.1038/nm.2015 · Cited by 1,812
Self-citationDangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer
Grivennikov, S. I., & Karin, M. (2010) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2009.11.005 · Cited by 1,160
Metadata
- Authors
- Kortylewski, M., Xin, H., Kujawski, M., Lee, H., Liu, Y., Harris, T., Drake, C., Pardoll, D., & Yu, H.
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2009-02
- Volume
- 15
- Issue
- 2
- Pages
- 114-123
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2114027214
- Cited by
- 474
- References
- 8
- FWCI
- 21.33
- Type
- journal article
- Language
- en
- Open access
- bronze
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