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Interferon- Inhibits STAT6 Signal Transduction and Gene Expression in Human Airway Epithelial Cells

Division of Allergy and Clinical Immunology and Department of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland; First Department of Internal Medicine, Showa University School of Medicine, Tokyo, Japan; Department of Microbiology and Immunology, Medical Center North, Vanderbilt University Medical School, Nashville, Tennessee; Department of Medicine and Microbiology, College of Physicians and Surgeons, Columbia University, New York, New York; and Division of Allergy and Immunology, Northwestern University Feinberg School of Medicine, Chicago, Illinois

Address correspondence to: Nicola M. Heller, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. E-mail: nheller{at}jhmi.edu

The activating and inhibitory cytokine signals that 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 (IL)-4 and IL-13, derived from T helper (Th)-2 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 (IFN)-, 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- 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- pretreatment, and this effect was dependent on the concentration of IFN- and time of exposure to IFN-. The functional activity of STAT6 was also completely inhibited by IFN-: IL-4–induced luciferase activity from a STAT6-driven reporter construct was suppressed, as was IL-4–induced expression of messenger RNA (mRNA) and protein for eotaxin-3, a STAT6-dependent gene implicated in allergic inflammation. We found that mRNA for suppressor of cytokine signaling (SOCS)–1 and (SOCS)–3, known inhibitors of IL-4 signaling, and IL-13 receptor 2, a potential inhibitor of IL-4 signaling, were both strongly induced by IFN- pretreatment. IFN- also increased the rate of decay of IL-4–induced eotaxin-3 mRNA. We conclude that there are multiple mechanisms by which IFN- regulates IL-4– and 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.

Abbreviations: bronchial epithelial growth medium, BEGM • CCAAT/enhancer binding protein, C/EBP • enzyme-linked immunosorbent assay, ELISA • concentration producing a half-maximum inhibition of effect, IC₅₀ • interferon, IFN • interleukin, IL • IFN-–inducible protein of 10 kD, IP-10 • Janus kinase, JAK • phosphate-buffered saline, PBS • PBS with Tween, PBST • polymerase chain reaction, PCR • receptor chain, R • sodium dodecyl sulfate, SDS • suppressor of cytokine signaling, SOCS • signal transducer and activator of transcription, STAT • T-helper, Th • untranslated region, UTR • wild-type STAT6 expression vector, WT-STAT6

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