The antiinflammatory cytokines IL-4 and IL- 10 are well recognized as important negative regulators of proinflammatory gene expression in mononuclear phagocytes. The intracellular mechanisms that mediate these responses appear to be multifactorial. IL-4 is able to suppress transcriptional activation of IFNgamma- and LPS-responsive genes; IL-4 activated STAT6 is required for the suppressive activity of IL-4. IL-4 and STAT6 appear to suppress transcription of select proinflammatory genes through the ability of STAT6 to sequester coactivator molecules that may be required for the transcriptional action of STAT1 and NFkappaB. In contrast, IL-10 suppresses the expression of genes induced in lipopolysaccharide (LPS)-stimulated macrophages by modulating both the transcription and stability of specific mRNAs. AU-rich nucleotide sequence elements in the 3'untranslated region of IL-10-sensitive genes confer sensitivity to IL-10-mediated destabilization. Thus mechanisms through which IL-10 and IL-4 act to dampen inflammatory responses are mechanistically distinct and involve diverse intracellular signaling pathways.