Regulation of the IL-23 and IL-12 Balance by Stat3 Signaling in the Tumor Microenvironment

Marcin Kortylewski, Hong Xin, Maciej Kujawski, Heehyoung Lee, Yong Liu, Timothy Harris, Charles Drake, Drew Pardoll, Hua Yu

Research output: Contribution to journalArticlepeer-review

Abstract

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-κB/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.

Original languageEnglish (US)
Pages (from-to)114-123
Number of pages10
JournalCancer cell
Volume15
Issue number2
DOIs
StatePublished - Feb 3 2009

Keywords

  • CELLCYCLE
  • MOLIMMUNO

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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