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Am. J. Respir. Cell Mol. Biol., Volume 24, Number 4, April, 2001 469-474

Genetic Ablation of the src Kinase p59fynT Exacerbates Pulmonary Inflammation in an Allergic Mouse Model

Elizabeth M. Kudlacz, Catharine J. Andresen, Michelle Salafia, Carrie A. Whitney, Barbara Naclerio, and Paul S. Changelian

Department of Immunology, Pfizer Global Research and Development, Groton, Connecticut

p59fynT is a protein tyrosine kinase in the src family that has been associated with and believed to function in the signaling of many receptors, including the T-cell receptor. A role for the kinase in antigen-driven pulmonary inflammation was examined using mice whose p59fynT gene had been genetically ablated. FynKO mice that were sensitized to ovalbumin exhibited a marked increase in bronchoalveolar lavage eosinophils and cytokines, including interleukin (IL)-4 and IL-5, relative to wild-type mice in response to antigen aerosol exposure. Ovalbumin-stimulated IL-5 production was also increased in cultured splenocytes derived from fynKO mice relative to wild-type mice, whereas interferon-gamma levels were unchanged. Diminished concanavalin A-stimulated IL-4 levels from fynKO splenocytes were consistent with reduced serum immunoglobulin (Ig)E levels observed in sensitized/saline aerosol-challenged animals and may reflect defective natural killer 1.1+ T cell development. Normalization of IgE levels in sensitized fynKO mice relative to wild-type mice occurred after repeat antigen challenge, which suggests a secondary source of IL-4. Overall, these data demonstrate fyn is a negative regulator of allergic airway inflammation in mice because its absence promotes a shift to a T helper-2 phenotype that may reflect the kinase's role in T-cell receptor signaling.

Abbreviations: bronchoalveolar lavage, BAL; BAL fluid, BALF; bovine serum albumin, BSA; concanavalin A, conA; eosinophil peroxidase, EPO; p59fynT-deficient mice, fynKO; interferon, IFN; immunoglobulin, Ig; interleukin, IL; natural killer, NK; phosphate-buffered saline, PBS; standard error of the mean, SEM; T-cell receptor, TCR; T helper, Th; white blood cell, WBC.




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