Interleukin-10 inhibits expression of both interferon alpha- and interferon gamma- induced genes by suppressing tyrosine phosphorylation of STAT1.
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).
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Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA.
Ansari
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P
Sakatsume
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Dickensheets
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H
Vazquez
N
N
Donnelly
R P
RP
Larner
A C
AC
Finbloom
D S
DS
D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004336:Drug Antagonism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology*; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D018909:src Homology Domains
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D011506:Proteins; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016753:Interleukin-10; D007371:Interferon-gamma