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Inhibition of IL‐4‐inducible gene expression in human monocytes by type I and type II interferons
Author(s) -
Dickensheets Harold L.,
Donnelly Raymond P.
Publication year - 1999
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.65.3.307
Subject(s) - biology , gene expression , gene , microbiology and biotechnology , monocyte , immunology , virology , genetics
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 Fc∊RIIb (CD23), 15‐lipoxygenase, IL‐1 receptor antagonist (IL‐1ra), and type I and type II IL‐1 receptors (IL‐1R). Type I interferons (IFN‐α and IFN‐β) and type Ii interferon (IFN‐γ) 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‐β and IFN‐γ to inhibit STAT6 activity provides an explanation for how IFNs can suppress IL‐4/IL‐13‐inducible gene expression. J. Leukoc. Biol. 65: 307–312; 1999.