Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment

Cancer Cell. 2009 Feb 3;15(2):114-23. doi: 10.1016/j.ccr.2008.12.018.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Gene Expression Regulation
  • Genes, Reporter
  • Immune System / physiology*
  • Interleukin-12 / genetics
  • Interleukin-12 / metabolism*
  • Interleukin-23 / genetics
  • Interleukin-23 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • Neoplasms* / immunology
  • Neoplasms* / pathology
  • Promoter Regions, Genetic
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction / physiology*
  • T-Lymphocytes, Regulatory / immunology


  • Interleukin-23
  • NF-kappa B
  • Receptors, Interleukin
  • STAT3 Transcription Factor
  • interleukin-23 receptor, mouse
  • Interleukin-12