Regulation of macrophage gene expression by pro- and anti-inflammatory cytokines

The anti-inflammatory cytokines IL-4 and IL-10 are well recognized as impor tant negative regulators of proinflammatory gene expression in mononuclear phagocytes. The intracellular mechanisms which mediate these responses appe ar to be multifactorial. IL-4 is able to markedly suppress transcriptional activation of IFN gamma-responsive genes and the promoter sequences require d for both IFN gamma and IL-4 sensitivity are identical. IFN gamma-activate d STAT1 and IL-4-activated STAT6 can both form complexes on the same regula tory sequence element; while STAT1 functions to promote transcription, STAT 6 is inactive. STAT6 is, however, required for the suppressive activity of IL-4. In this model, IL-4 appears to suppress IFN gamma-inducible proinflam matory gene expression through the ability of STAT6 to compete with STAT1 f or occupancy of promoter sites necessary for IFN gamma-induced transcriptio nal initiation. In a second model, IL-10 suppresses the expression of genes induced in LPS-stimulated macrophages through a pathway involving destabil ization of specific mRNAs. We have demonstrated that nucleotide sequences i n the 3'-untranslated region of an IL-10-sensitive gene can both destabiliz e a stable reporter mRNA (CAT) and confer sensitivity to IL-10-mediated des tabilization. Deletion and site-specific mutagenesis have mapped this to an AU-rich sequence motif similar to that found in many cytokine and growth f actor mRNAs. IL-10 is able to modulate the activity of proteins capable of binding to this sequence and one or more of these may regulate the rate of mRNA degradation. Thus mechanisms through which IL-10 and IL-4 act to dampe n inflammatory responses are mechanistically distinct and involve diverse i ntracellular signaling pathways. Copyright (C) 2000 S,Karger AG. Basel.