Inhibition of IL-4-inducible gene expression in human monocytes by type I and type II interferons

The Th2-type cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13), induce expression of a distinct subset of genes in human monocytes, including FcepsilonRIIb (CD23), 15-lipoxygenase, IL-1 receptor antagonist (IL-1ra), and type I and type II IL-1 receptors (IL-1R). Type I interferons (IFN-alpha and IFN-beta) and type II interferon (IFN-gamma) inhibit induction of these genes by IL-4 and IL-13. However, the mechanism by which IFNs mediate this inhibition has not been defined. In this overview, we discuss the role of the transcription factor, STAT6 (signal transducer and activator of transcription-6) in mediating IL-4- and IL-13-induced gene expression in monocytes. We also discuss our recent findings that type I and type II IFNs suppress IL-4/IL-13-inducible gene expression by inhibiting tyrosine phosphorylation and nuclear translocation of STAT6. The ability of type I and type II IFNs to inhibit IL-4/IL-13-induced STAT6 activity is dose- and time-dependent, and is not unique to monocytes because IFNs induce the same effects in fibroblasts. Inhibition of STAT6 activity is not evident unless cells are preincubated with IFN for at least 1 h before IL-4 stimulation. Furthermore, inhibition can be blocked by actinomycin D, indicating a requirement for de novo transcription. We propose a model in which stimulation of monocytes by IFN activates de novo synthesis of an inhibitory factor, possibly one or more members of the SOCS/ SSI/CIS gene family, capable of suppressing activation of STAT6 by IL-4 and IL-13. Because STAT6 activation plays an essential role in IL-4/IL-13-induced gene expression, the ability of IFN-beta and IFN-gamma to inhibit STAT6 activity provides an explanation for how IFNs can suppress IL-4/IL-13-inducible gene expression.