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

• Published in: Blood Vol. 93; no. 5; pp. 1456 - 1463
• Main Authors: ITO, S, ANSARI, P, SAKATSUME, M, DICKENSHEETS, H, VAZQUEZ, N, DONNELLY, R. P, LARNER, A. C, FINBLOOM, D. S
• Format: Journal Article
• Language: English
• Published: Washington, DC The Americain Society of Hematology 01.03.1999
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Biological and medical sciences; Cells, Cultured; DNA-Binding Proteins - metabolism; Drug Antagonism; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation - drug effects; Humans; Immunobiology; Interferon-alpha - pharmacology; Interferon-gamma - pharmacology; Interleukin-10 - pharmacology; Lymphokines, interleukins ( function, expression); Monocytes - immunology; Monocytes - metabolism; Phosphorylation; Proteins - genetics; Regulatory factors and their cellular receptors; Repressor Proteins; Signal Transduction - drug effects; Signal Transduction - genetics; src Homology Domains; STAT1 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Th1 Cells - immunology; Th2 Cells - immunology; Trans-Activators - metabolism; Transcription Factors; Human; Monocyte; Transcription; Alpha interferon; Cell biology; Helper cell; Cellular immunity; Gene expression; Signal transduction; Activator; Interleukin 10; T-Lymphocyte; Physiology; Gamma interferon
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.v93.5.1456.404a34_1456_1463

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).