The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/3/939/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 6, March 16, 1998 939-948

Articles

Signal Transducer and Activator of Transcription Factor 6 (Stat6)-deficient Mice Are Protected from Antigen-induced Airway Hyperresponsiveness and Mucus Production

Douglas Kuperman*, Brian Schofield*, Marsha Wills-Karp*, and Michael J. Grusby{ddagger},§

From the * Department of Environmental Health Sciences, Johns Hopkins School of Public Health, Baltimore, Maryland 21205; and the {ddagger} Department of Immunology and Infectious Diseases, Harvard School of Public Health, and § Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115

The pleiotropic cytokine interleukin 4 (IL-4) has been shown to regulate many processes thought to be important in the allergic diathesis. To determine the mechanism(s) by which IL-4 mediates allergic airway responses to inhaled allergens, we compared the effects of antigen sensitization and challenge on the development of allergic airway responses in mice in which the gene for the signal transducer and activator of transcription factor 6 (Stat6) was disrupted to those of their wild-type littermates. Strikingly, Stat6-deficient mice failed to develop airway hyperresponsiveness (AHR), which was observed in their wild-type littermates after allergen provocation. Moreover, antigen-induced increases in mucus-containing cells were found to be completely Stat6 dependent. Consistent with the lack of Th2 cytokine responses in Stat6-deficient mice, no ovalbumin-specific immunoglobulin (Ig)E was detected in their serum. In contrast, Stat6 signaling only partially mediated antigen-induced eosinophilia with no role in vascular adhesion molecule 1 expression. These results indicate that Stat6 signal transduction is critical in the development of allergen-induced AHR and that agents that specifically inhibit this pathway may provide a novel strategy for the treatment of allergic disorders.

Address correspondence to Marsha Wills-Karp, Johns Hopkins School of Hygiene and Public Health, 615 North Wolfe Street, Baltimore, MD 21205. Phone: 410-614-5447; Fax: 410-955-0299; E-mail: mkarp{at}welchlink.welch.jhu.edu

1 Abbreviations used in this paper: Ach, acetylcholine chloride; AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; IRS, insulin receptor substrate; PDGF, platelet-derived growth factor; Stat6, signal transducer and activator of transcription factor 6; VCAM-1, vascular cell adhesion molecule 1.


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