Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 372K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Blaeser, F. Articles by Chatila, T. A. Search for Related Content PubMed PubMed Citation Articles by Blaeser, F. Articles by Chatila, T. A. Social Bookmarking                            What's this?

Targeted Inactivation of the IL-4 Receptor Chain I4R Motif Promotes Allergic Airway Inflammation

Frank Blaeser¹, Paul J. Bryce², Nga Ho¹, Vidya Raman¹, Fatma Dedeoglu², Debra D. Donaldson³, Raif S. Geha², Hans C. Oettgen² and Talal A. Chatila^1,4

¹ Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110
² Department of Pediatrics, Harvard Medical School, Boston, MA 02115
³ Department of Respiratory Disease, Wyeth Research, Cambridge, MA 02140
⁴ Department of Pathology and Immunology and the Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110

Address correspondence to Talal A. Chatila, Dept. of Pediatrics, The David Geffen School of Medicine, University of California at Los Angeles, 10833 Le Conte Ave., Los Angeles, CA 90095-1752. Phone: (310) 825-4125; Fax: (310) 206-4584; email: Tchatila{at}mednet.ucla.edu

The insulin/interleukin-4 (IL-4) receptor (I4R) motif mediates the association of insulin receptor substrate (IRS)-2 with the interleukin-4 (IL-4)R chain and transduces mitogenic signals in response to IL-4. Its physiological functions were analyzed in mice with a germline point mutation that changed the motif's effector tyrosine residue into phenylalanine (Y500F). The Y500F mutation abrogated IRS-2 phosphorylation and impaired IL-4–induced CD4⁺ T lymphocyte proliferation but left unperturbed Stat6 activation, up-regulation of IL-4-responsive gene products, and Th cell differentiation under Th2 polarizing conditions. However, in vivo the Y500F mutation was associated with increased allergen-induced IgE production, airway responsiveness, tissue eosinophilia, and mucus production. These results define an important role for the I4R motif in regulating allergic inflammation.

Key Words: interleukin 4 receptor • targeted mutagenesis • immunoglobulin E • insulin receptor substrate • asthma

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Tachdjian, R., Mathias, C., Al Khatib, S., Bryce, P. J., Kim, H. S., Blaeser, F., O'Connor, B. D., Rzymkiewicz, D., Chen, A., Holtzman, M. J., Hershey, G. K., Garn, H., Harb, H., Renz, H., Oettgen, H. C., Chatila, T. A. (2009). Pathogenicity of a disease-associated human IL-4 receptor allele in experimental asthma. JEM 206: 2191-2204 [Abstract] [Full Text]  
• Wills-Karp, M., Finkelman, F. D. (2008). Untangling the Complex Web of IL-4- and IL-13-Mediated Signaling Pathways. Sci Signal 1: pe55-pe55 [Abstract] [Full Text]  
• Heller, N. M., Qi, X., Junttila, I. S., Shirey, K. A., Vogel, S. N., Paul, W. E., Keegan, A. D. (2008). Type I IL-4Rs Selectively Activate IRS-2 to Induce Target Gene Expression in Macrophages. Sci Signal 1: ra17-ra17 [Abstract] [Full Text]  
• Wei, L. H., Yang, Y., Wu, G., Ignarro, L. J. (2008). IL-4 and IL-13 upregulate ornithine decarboxylase expression by PI3K and MAP kinase pathways in vascular smooth muscle cells. Am. J. Physiol. Cell Physiol. 294: C1198-C1205 [Abstract] [Full Text]  
• Stephenson, L. M., Park, D.-S., Mora, A. L., Goenka, S., Boothby, M. (2005). Sequence Motifs in IL-4R{alpha} Mediating Cell-Cycle Progression of Primary Lymphocytes. J. Immunol. 175: 5178-5185 [Abstract] [Full Text]  
• Lin, D. A., Boyce, J. A. (2005). IL-4 Regulates MEK Expression Required for Lysophosphatidic Acid-Mediated Chemokine Generation by Human Mast Cells. J. Immunol. 175: 5430-5438 [Abstract] [Full Text]  
• Zhou, X., Trudeau, J. B., Schoonover, K. J., Lundin, J. I., Barnes, S. M., Cundall, M. J., Wenzel, S. E. (2005). Interleukin-13 augments transforming growth factor-{beta}1-induced tissue inhibitor of metalloproteinase-1 expression in primary human airway fibroblasts. Am. J. Physiol. Cell Physiol. 288: C435-C442 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS