Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment.
Interactions between tumor and immune cells either enhance or inhibit cancer progression. We show here that Stat3 signaling within the tumor microenvironment induces a procarcinogenic cytokine, IL-23, while inhibiting a central anticarcinogenic cytokine, IL-12, thereby shifting the balance of tumor immunity toward 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-kappaB/c-Rel-dependent IL-12/p35 gene expression in tumor-associated dendritic cells. Tumor-associated regulatory T cells (Tregs) express IL-23 receptor, 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 procarcinogenic immune responses while inhibiting IL-12-dependent antitumor immunity.
Kortylewski
Marcin
M
Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA.
Xin
Hong
H
Kujawski
Maciej
M
Lee
Heehyoung
H
Liu
Yong
Y
Harris
Timothy
T
Drake
Charles
C
Pardoll
Drew
D
Yu
Hua
H
D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007107:Immune System / Q000502:physiology*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D011401:Promoter Regions, Genetic; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D053759:Interleukin-23; D016328:NF-kappa B; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C528688:interleukin-23 receptor, mouse; D018664:Interleukin-12