J. Exp. Med., Volume 187, Number 6, March 16, 1998 939-948

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

By Douglas Kuperman,^* Brian Schofield,^* Marsha Wills-Karp,^* and Michael J. Grusby^§

From the ^* Department of Environmental Health Sciences, Johns Hopkins School of Public Health, Baltimore, Maryland 21205; and the  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.

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• Dickensheets, H. L., Venkataraman, C., Schindler, U., Donnelly, R. P. (1999). Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression. Proc. Natl. Acad. Sci. USA 96: 10800-10805 [Abstract] [Full Text]  
• Chin, J. E., Hatfield, C. A., Winterrowd, G. E., Krzesicki, R. F., Shull, K. L., Fidler, S. F., Kolbasa, K. P., Brashler, J. R., Griffin, R. L., Fleming, W. E., Justen, J. M., Banitt, L. S., Bundy, G. L., Richards, I. M. (1999). Preclinical Evaluation of Anti-inflammatory Activities of the Novel Pyrrolopyrimidine PNU-142731A, a Potential Treatment for Asthma. J. Pharmacol. Exp. Ther. 290: 188-195 [Abstract] [Full Text]  
• Kato, Y., Manabe, T., Tanaka, Y., Mochizuki, H. (1999). Effect of an Orally Active Th1/Th2 Balance Modulator, M50367, on IgE Production, Eosinophilia, and Airway Hyperresponsiveness in Mice. J. Immunol. 162: 7470-7479 [Abstract] [Full Text]  
• Levings, M. K., Bessette, D. C., Schrader, J. W. (1999). Interleukin-4 Synergizes With Raf-1 to Promote Long-Term Proliferation and Activation of c-jun N-terminal Kinase. Blood 93: 3694-3702 [Abstract] [Full Text]  
• Cohn, L., Homer, R. J., MacLeod, H., Mohrs, M., Brombacher, F., Bottomly, K. (1999). Th2-Induced Airway Mucus Production Is Dependent on IL-4R{alpha}, But Not on Eosinophils. J. Immunol. 162: 6178-6183 [Abstract] [Full Text]  
• Dabbagh, K., Takeyama, K., Lee, H.-M., Ueki, I. F., Lausier, J. A., Nadel, J. A. (1999). IL-4 Induces Mucin Gene Expression and Goblet Cell Metaplasia In Vitro and In Vivo. J. Immunol. 162: 6233-6237 [Abstract] [Full Text]  
• Akira, S. (1999). Functional Roles of STAT Family Proteins: Lessons from Knockout Mice. Stem Cells 17: 138-146 [Abstract] [Full Text]  
• Levings, M. K., Schrader, J. W. (1999). IL-4 Inhibits the Production of TNF-{alpha} and IL-12 by STAT6-Dependent and -Independent Mechanisms. J. Immunol. 162: 5224-5229 [Abstract] [Full Text]  
• Wills-Karp, M., Luyimbazi, J., Xu, X., Schofield, B., Neben, T. Y., Karp, C. L., Donaldson, D. D. (1998). Interleukin-13: Central Mediator of Allergic Asthma. Science 282: 2258-2261 [Abstract] [Full Text]  
• Dent, A. L., Hu-Li, J., Paul, W. E., Staudt, L. M. (1998). T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. Proc. Natl. Acad. Sci. USA 95: 13823-13828 [Abstract] [Full Text]  
• Cohn, L., Tepper, J. S., Bottomly, K. (1998). Cutting Edge: IL-4-Independent Induction of Airway Hyperresponsiveness by Th2, But Not Th1, Cells. J. Immunol. 161: 3813-3816 [Abstract] [Full Text]  
• Daniel, C., Salvekar, A., Schindler, U. (2000). A Gain-of-function Mutation in STAT6. J. Biol. Chem. 275: 14255-14259 [Abstract] [Full Text]  

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