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PMID: 10485906 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 19 ·1999-09-14 ·Pages 10800-5

Dickensheets HL, Venkataraman C, Schindler U, Donnelly RP

Abstract

Interferons (IFNs) inhibit induction by IL-4 of multiple genes in human monocytes. However, the mechanism by which IFNs mediate this inhibition has not been defined. IL-4 activates gene expression by inducing tyrosine phosphorylation, homodimerization, and nuclear translocation of the latent transcription factor, STAT6 (signal transducer and activator of transcription-6). STAT6-responsive elements are characteristically present in the promoters of IL-4-inducible genes. Because STAT6 activation is essential for IL-4-induced 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. Pretreatment 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 by IL-4. This inhibition was associated with decreased tyrosine phosphorylation 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. Furthermore, 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, markedly suppressed trans-activation of an IL-4-inducible reporter as well as IL-6- and IFN-gamma-induced reporter gene activity. These findings demonstrate that IFNs inhibit IL-4-induced activation of STAT6 and STAT6-dependent gene expression, at least in part, by inducing expression of SOCS-1.

MeSH Terms
Carrier Proteins/metabolism Cell Line Dactinomycin/pharmacology Humans Interferon-beta/metabolism Interferon-gamma/metabolism Interferons/metabolism Interleukin-13/metabolism Interleukin-4/metabolism Interleukin-6/metabolism Intracellular Signaling Peptides and Proteins Kinetics Monocytes/metabolism Phosphorylation Protein Synthesis Inhibitors/pharmacology Repressor Proteins STAT6 Transcription Factor Suppressor of Cytokine Signaling 1 Protein Suppressor of Cytokine Signaling Proteins Time Factors Trans-Activators/antagonists & inhibitors,metabolism Transcription, Genetic Transfection Translocation, Genetic
Chemicals
Carrier Proteins Interleukin-13 Interleukin-6 Intracellular Signaling Peptides and Proteins Protein Synthesis Inhibitors Repressor Proteins SOCS1 protein, human STAT6 Transcription Factor STAT6 protein, human Suppressor of Cytokine Signaling 1 Protein Suppressor of Cytokine Signaling Proteins Trans-Activators Dactinomycin Interleukin-4 Interferon-beta Interferon-gamma Interferons
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Dickensheets H L
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Venkataraman C
Schindler U
Donnelly R P
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.19.10800
Published
1999-09-14
Pages
10800-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC17963
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.96.19.10800 PMC Full Text View journal details
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