IFN-gamma and IL-10 inhibit induction of IL-1 receptor type I and type II gene expression by IL-4 and IL-13 in human monocytes.
The Th2-type cytokines IL-4 and IL-13 induce expression of a distinct subset of genes in human monocytes. These include Fc epsilonRII (CD23), 15-lipoxygenase, IL-1 receptor antagonist (IL-1ra), and type I and type II IL-1 receptors (IL-1R). IFN-gamma has been shown to inhibit induction of CD23 and 15-lipoxygenase in monocytes; however, the effects of IFN-gamma on type I and type II IL-1R gene expression have not been defined. We examined the effects of IFN-gamma on both basal and IL-4/IL-13-induced IL-1R gene expression in primary monocytes. IL-4 and IL-13 induced dose- and time-dependent increases in IL-1RI and IL-1RII mRNA levels. IFN-gamma decreased basal expression as well as the induction of these genes by IL-4 and IL-13. Inhibition of IL-1RI and IL-1RII mRNA levels by IFN-gamma was transcriptionally mediated, and correlated directly with decreased production of soluble IL-1RII. Furthermore, the ability to suppress IL-1RI and IL-1RII mRNA levels was not unique to IFN-gamma because IL-10 also inhibited expression of these genes in IL-4/IL-13-stimulated monocytes. Inhibition of IL-1R gene expression by IFN-gamma and IL-10 was not due to down-regulation of surface IL-4R because pretreatment with these cytokines did not decrease the number of IL-4 binding sites per cell. However, suppression of IL-1R gene expression by IFN-gamma and IL-10 was associated with decreased tyrosine phosphorylation and nuclear translocation of the IL-4/IL-13-inducible transcription factor, Stat6, suggesting a potential mechanism by which IFN-gamma and IL-10 may mediate their suppressive effects. These findings demonstrate that certain cytokines, including IFN-gamma and IL-10, antagonize the ability of IL-4 and IL-13 to induce increased expression of the IL-1RI and IL-1RII genes in monocytes.
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Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Donnelly
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RP
D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D016753:Interleukin-10 / Q000494:pharmacology*; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
D018793:Interleukin-13; D017472:Receptors, Interleukin-1; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015534:Trans-Activators; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma