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Published ahead of print on August 5, 2004, doi:10.1165/rcmb.2004-0195OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 5, November 2004, 573-582

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Submitted on June 18, 2004
Revised on August 4, 2004

Interferon-{gamma} inhibits STAT6 signal transduction and gene expression in human airway epithelial cells

Nicola M Heller1*, Satoshi Matsukura2, Steve N Georas3, Mark R Boothby4, Paul B Rothman5, Cristiana Stellato1, and Robert P Schleimer6

1 Allergy and Clinical Immunology, The Johns Hopkins University, Baltimore, Maryland, USA, 2 First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan, 3 Department of Pulmonary and Critical Care Medicine, The Johns Hopkins University Asthma and Allergy Center, Baltimore, Maryland, USA, 4 Department of Microbiology and Immunology, Vanderbilt University Medical School, Nashville, Tennessee, USA, 5 Department of Medicine and Microbiology, Columbia University, New York, New York, USA, 6 Division of Allergy and Immunology, Northwestern University, Chicago, Illinois, USA

* To whom correspondence should be addressed. E-mail: nheller{at}jhmi.edu.

The activating and inhibitory cytokine signals which act upon epithelial cells in the human lung are critically important for controlling the production of inflammatory mediators from those cells in the context of allergic disease. The cytokines interleukin-4 (IL-4) and IL-13 derived from T helper 2- (Th2-) cells and other cell types are potent inducers of epithelial cell expression of a host of inflammatory molecules, including the chemokines eotaxin-1, -2 and -3. Intracellular signal transduction in response to IL-4/IL-13 occurs largely through activation of Signal Transducer and Activator of Transcription 6 (STAT6). Interferon-{gamma} (IFN-{gamma}), a Th1-type cytokine, has opposing effects to IL-4/IL-13 in various cell types, including T-cells, B-cells, endothelium and epithelium. In this study, we demonstrate that IL-4-induced STAT6 activation was inhibited profoundly by 24 h pretreatment with IFN-{gamma} in human primary airway epithelial cell cultures. Using Western blotting, we showed that the levels of both cytoplasmic and nuclear-localized phospho-STAT6 were reduced by IFN-{gamma} pretreatment and this effect was dependent on the concentration of IFN-{gamma} and time of exposure to IFN-{gamma}. The functional activity of STAT6 was also completely inhibited by IFN-{gamma}: IL-4-induced uciferase activity from a STAT6-driven reporter construct was suppressed, as was IL-4-induced expression of mRNA and protein for eotaxin-3, a STAT6-dependent gene implicated in allergic inflammation. We found that mRNA for SOCS-1 and SOCS-3, known inhibitors of IL-4 signaling, and IL-13R{alpha}2, a potential inhibitor of IL-4 signaling, were both strongly induced by IFN-{gamma} pretreatment. IFN-{gamma} also increased the rate of decay of IL-4-induced eotaxin-3 mRNA. We conclude that there are multiple mechanisms by which IFN-{gamma} regulates IL-4-/STAT6-dependent signaling and gene expression in airway epithelial cells. These observations have important implications for the regulation of epithelial cell activation by the balance of Th1/Th2-type cytokines in the airways in allergic disease.




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