Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma- induced genes by suppressing tyrosine phosphorylation of STAT1

Blood. 1999 Mar 1;93(5):1456-63.

Abstract

Interleukin-10 (IL-10) helps maintain polarized T-helper cells in a T-helper lymphocyte 2 (Th2) phenotype. Part of this process involves the prevention of the development of Th1 cells, which are a primary source of interferon gamma (IFNgamma), a potent activator of monocytes and an inhibitor of Th2 proliferation. Because monocytes and macrophages are important mediators of Th1-type responses, such as delayed-type hypersensitivity, we sought to determine if IL-10 could directly mediate inhibition of IFNgamma- and IFNalpha-induced gene expression in these cells. Highly purified monocytes were incubated with IL-10 for 60 to 90 minutes before the addition of IFNgamma or IFNalpha. IL-10 preincubation resulted in the inhibition of gene expression for several IFN-induced genes, such as IP-10, ISG54, and intercellular adhesion molecule-1. The reduction in gene expression resulted from the ability of IL-10 to suppress IFN-induced assembly of signal transducer and activator of transcription (STAT) factors to specific promoter motifs on IFNalpha- and IFNgamma-inducible genes. This was accomplished by preventing the IFN-induced tyrosine phosphorylation of STAT1, a component of both IFNalpha- and IFNgamma-induced DNA binding complexes. Therefore, IL-10 can directly inhibit STAT-dependent early response gene expression induced by both IFNalpha and IFNgamma in monocytes by suppressing the tyrosine phosphorylation of STAT1. This may occur through the ability of IL-10 to induce expression of the gene, suppressor of cytokine signaling 3 (SOCS3).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • DNA-Binding Proteins / metabolism*
  • Drug Antagonism
  • Gene Expression Regulation / drug effects*
  • Humans
  • Interferon-alpha / pharmacology*
  • Interferon-gamma / pharmacology*
  • Interleukin-10 / pharmacology*
  • Monocytes / immunology
  • Monocytes / metabolism*
  • Phosphorylation
  • Proteins / genetics
  • Repressor Proteins*
  • STAT1 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Th1 Cells / immunology
  • Th2 Cells / immunology
  • Trans-Activators / metabolism*
  • Transcription Factors*
  • src Homology Domains

Substances

  • DNA-Binding Proteins
  • Interferon-alpha
  • Proteins
  • Repressor Proteins
  • SOCS3 protein, human
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Trans-Activators
  • Transcription Factors
  • Interleukin-10
  • Interferon-gamma