Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression

Interferons (IFNs) inhibit induction by IL-4 defined. IL-4 activates gene e xpression by inducing tryosine of multiple genes in human monocytes. Howeve r, the mechanism by which IFNs mediate this inhibition has not been phospho rylation, homodimerization, and nuclear translocation of the latent transcr iption factor, STAT6 (signal transducer and activator of transcription-6). STAT6-responsive elements are characteristically present in the promoters o f IL-4-inducible genes. Because STAT6 activation is essential for IL-4-indu ced gene expression, we examined the ability of type I and type II IFNs to regulate activation of STAT6 by IL-4 in primary human monocytes. Pretreatme nt of monocytes with IFN-beta or IFN-gamma, but not IL-1, IL-2, macrophage colony-stimulating factor, granulocyte/macrophage colony-stimulating factor , IL-6, or transforming growth factor beta suppressed activation of STAT6 b y IL-4. This inhibition was associated with decreased tyrosine phosphorylat ion and nuclear translocation of STAT6 and was not evident unless the cells were preincubated with IFN for at least 1 hr before IL-4 stimulation. Furt hermore, inhibition by IFN could be blocked by cotreatment with actinomycin D and correlated temporally with induction of the JAK/STAT inhibitory gene , SOCS-1, Forced expression of SOCS-1 in a macrophage cell line, RAW264, ma rkedly suppressed trans-activation of an IL-4-inducible reporter as well as IL-6- and IFN-gamma-induced reporter gene activity. These findings demonst rate that IFNs inhibit IL-4-induced activation of STAT6 and STAT6-dependent gene expression, at least in part, by inducing expression of SOCS-1.