Reprogramming of IL-10 activity and signaling by IFN-gamma

J Immunol. 2003 Nov 15;171(10):5034-41. doi: 10.4049/jimmunol.171.10.5034.


One important mechanism of cross-regulation by opposing cytokines is inhibition of signal transduction, including inhibition of Janus kinase-STAT signaling by suppressors of cytokine signaling. We investigated whether IFN-gamma, a major activator of macrophages, inhibited the activity of IL-10, an important deactivator. Preactivation of macrophages with IFN-gamma inhibited two key anti-inflammatory functions of IL-10, the suppression of cytokine production and of MHC class II expression. Gene expression profiling showed that IFN-gamma broadly suppressed the ability of IL-10 to induce or repress gene expression. Although IFN-gamma induced expression of suppressor of cytokine signaling proteins, IL-10 signal transduction was not suppressed and IL-10 activation of Janus kinases and Stat3 was preserved. Instead, IFN-gamma switched the balance of IL-10 STAT activation from Stat3 to Stat1, with concomitant activation of inflammatory gene expression. IL-10 activation of Stat1 required the simultaneous presence of IFN-gamma. These results demonstrate that IFN-gamma operates a switch that rapidly regulates STAT activation by IL-10 and alters macrophage responses to IL-10. Dynamic regulation of the activation of different STATs by the same cytokine provides a mechanism by which cells can integrate and balance signals delivered by opposing cytokines, and extends our understanding of cross-regulation by opposing cytokines to include reprogramming of signaling and alteration of function.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Adjuvants, Immunologic / physiology
  • Cell Line
  • Cells, Cultured
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology
  • Drug Synergism
  • Gene Expression Regulation / immunology
  • Humans
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / physiology
  • Interferon-gamma / pharmacology*
  • Interferon-gamma / physiology
  • Interleukin-10 / antagonists & inhibitors
  • Interleukin-10 / metabolism*
  • Interleukin-10 / physiology*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Macrophage Activation / immunology
  • STAT1 Transcription Factor
  • STAT3 Transcription Factor
  • Signal Transduction / immunology*
  • Trans-Activators / biosynthesis
  • Trans-Activators / metabolism
  • Trans-Activators / physiology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Up-Regulation / immunology


  • Adjuvants, Immunologic
  • DNA-Binding Proteins
  • Inflammation Mediators
  • Lipopolysaccharides
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Trans-Activators
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma