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 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.
Kudlacz
E M
EM
Department of Immunology, Pfizer Global Research and Development, Groton, Connecticut 06340, USA. elizabeth_m_kudlacz@groton.pfizer.com
Andresen
C J
CJ
Salafia
M
M
Whitney
C A
CA
Naclerio
B
B
Changelian
P S
PS
D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D003208:Concanavalin A / Q000494:pharmacology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism*; D007073:Immunoglobulin E / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000276:immunology; D051076:Proto-Oncogene Proteins c-fyn; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics* / Q000276:immunology
D000941:Antigens; D015848:Interleukin-5; D011518:Proto-Oncogene Proteins; D003208:Concanavalin A; D015847:Interleukin-4; D007073:Immunoglobulin E; D010047:Ovalbumin; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases