The Journal of Experimental Medicine
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Published online 1 June 2004 doi:10.1084/jem.20040382
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 11, 1491-1502
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Negative Regulation of Immunoglobulin E–dependent Allergic Responses by Lyn Kinase

Sandra Odom1, Gregorio Gomez1, Martina Kovarova1, Yasuko Furumoto1, John J. Ryan1,2, Harry V. Wright2, Claudia Gonzalez-Espinosa1,3, Margaret L. Hibbs4, Kenneth W. Harder4, and Juan Rivera1

1 Molecular Inflammation Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892
2 Department of Biology, Virginia Commonwealth University, Richmond, VA 23284
3 Pharmacobiology Department, CINVESTAV Zona Sur, Mexico D.F., CP 14330 Mexico
4 Ludwig Institute for Cancer Research, Melbourne Tumor Biology Branch, Victoria 3050, Australia

Address correspondence to Juan Rivera, National Institute of Arthritis and Musculoskeletal and Skin Diseases/National Institutes of Health, Building 10, Room 9N228, Bethesda, MD 20892. Phone: (301) 496-7592; Fax: (301) 480-1580; email: juan_rivera{at}nih.gov

A role for Lyn kinase as a positive regulator of immunoglobulin (Ig)E-dependent allergy has long been accepted. Contrary to this belief, Lyn kinase was found to have an important role as a negative regulator of the allergic response. This became apparent from the hyperresponsive degranulation of lyn–/– bone marrow–derived mast cells, which is driven by hyperactivation of Fyn kinase that occurs, in part, through the loss of negative regulation by COOH-terminal Src kinase (Csk) and the adaptor, Csk-binding protein. This phenotype is recapitulated in vivo as young lyn–/– mice showed an enhanced anaphylactic response. In vivo studies also demonstrated that as lyn–/– mice aged, their serum IgE increased as well as occupancy of the high affinity IgE receptor (Fc{epsilon}RI). This was mirrored by increased circulating histamine, increased mast cell numbers, increased cell surface expression of the high affinity IgE receptor (Fc{epsilon}RI), and eosinophilia. The increased IgE production was not a consequence of increased Fyn kinase activity in lyn–/– mice because both lyn–/– and lyn–/– fyn–/– mice showed high IgE levels. Thus, lyn–/– mice and mast cells thereof show multiple allergy-associated traits, causing reconsideration of the possible efficacy in therapeutic targeting of Lyn in allergic disease.

Key Words: Lyn kinase • IgE • mast cells • allergy • degranulation

S. Odom, G. Gomez, K.W. Harder, and J. Rivera contributed equally to this work.

The online version of this article contains supplemental material.

Abbreviations used in this paper: BMMC, bone marrow–derived mast cell; Cbp, COOH-terminal Src kinase–binding protein; Csk, COOH-terminal Src kinase; GFP, green fluorescent protein; HRP, horseradish peroxidase; HSA, human serum albumin; IVK, in vitro kinase; PI3K, phosphatidylinositol 3-OH kinase; PSA, passive systemic anaphylaxis; SCF, stem cell factor; Src PTK, Src family protein tyrosine kinase.


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