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.