Genetic ablation of the src kinase p59fynT exacerbates pulmonary inflammation in an allergic mouse model

p59fynT is a protein tyrosine kinase in the src family that has been associ ated with and believed to function in the signaling of many receptors, incl uding the T-cell receptor. A role for the kinase in antigen-driven pulmonar y inflammation was examined using mice whose p59fynT gene had been genetica lly ablated. FynKO mice that were sensitized to ovalbumin exhibited a marke d increase in bronchoalveolar lavage eosinophils and cytokines, including i nterleukin (IL)-4 and IL-5, relative to wild-type mice in response to antig en aerosol exposure. Ovalbumin-stimulated IL-5 production was also increase d in cultured splenocytes derived from fynKO mice relative to wild-type mic e, whereas interferon-gamma levels were unchanged. Diminished concanavalin A-stimulated IL-4 levels from fynKO splenocytes were consistent with reduce d serum immunoglobulin (Ig)E levels observed in sensitized/saline aerosol-c hallenged animals and may reflect defective natural killer 1.1(+) T cell de velopment. Normalization of IgE levels in sensitized fynKO mice relative to wild-type mice occurred after repeat antigen challenge, which suggests a s econdary source of IL-4. Overall, these data demonstrate fyn is a negative regulator of allergic: airway inflammation in mice because its absence prom otes a shift to a T helper-2 phenotype that may reflect the kinase's role i n T-cell receptor signaling.