SOCS3 transactivation by PPARγ prevents IL-17-driven cancer growth

Cancer Res. 2013 Jun 15;73(12):3578-90. doi: 10.1158/0008-5472.CAN-12-4018. Epub 2013 Apr 25.

Abstract

Activation of the transcription factor PPARγ by the n-3 fatty acid docosahexaenoic acid (DHA) is implicated in controlling proinflammatory cytokine secretion, but the intracellular signaling pathways engaged by PPARγ are incompletely characterized. Here, we identify the adapter-encoding gene SOCS3 as a critical transcriptional target of PPARγ. SOCS3 promoter binding and gene transactivation by PPARγ was associated with a repression in differentiation of proinflammatory T-helper (TH)17 cells. Accordingly, TH17 cells induced in vitro displayed increased SOCS3 expression and diminished capacity to produce interleukin (IL)-17 following activation of PPARγ by DHA. Furthermore, naïve CD4 T cells derived from mice fed a DHA-enriched diet displayed less capability to differentiate into TH17 cells. In two different mouse models of cancer, DHA prevented tumor outgrowth and angiogenesis in an IL-17-dependent manner. Altogether, our results uncover a novel molecular pathway by which PPARγ-induced SOCS3 expression prevents IL-17-mediated cancer growth.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / drug effects
  • Cell Line, Tumor
  • Diet
  • Docosahexaenoic Acids / administration & dosage
  • Docosahexaenoic Acids / pharmacology
  • Female
  • Interleukin-17 / metabolism
  • Mammary Neoplasms, Experimental / genetics*
  • Mammary Neoplasms, Experimental / pathology
  • Mammary Neoplasms, Experimental / prevention & control
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Nude
  • PPAR gamma / agonists
  • PPAR gamma / genetics*
  • PPAR gamma / metabolism
  • Promoter Regions, Genetic / genetics
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics*
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Th17 Cells / drug effects
  • Th17 Cells / metabolism
  • Transcriptional Activation*
  • Tumor Burden / drug effects
  • Tumor Burden / genetics

Substances

  • Interleukin-17
  • PPAR gamma
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Docosahexaenoic Acids