Interleukin-2-inducible T cell kinase regulates mast cell degranulation and acute allergic responses.
Bruton's tyrosine kinase (Btk) is thought to positively regulate mast cell activation, implying a role in allergic responses. We have compared acute and late phase allergic airway reactions in mice lacking either Btk or interleukin-2-inducible T cell kinase (Itk), another Tec kinase expressed in mast cells. Btk(-/-) mice showed minor protection against allergic symptoms when challenged with allergen via the airways. In sharp contrast, both acute and late phase inflammatory allergic responses were markedly reduced in Itk(-/-) mice. Notably, airway mast cell degranulation in Itk(-/-) mice was severely impaired, despite wild-type levels of allergen-specific IgE and IgG1. The degranulation defect was confirmed in DNP-conjugated human serum albumin-challenged mice passively sensitized with anti-DNP IgE antibodies, and was also observed after direct G-protein stimulation with the mast cell secretagogue c48/80. Moreover, late phase inflammatory changes, including eosinophilia, lymphocyte infiltration, and Th2 cytokine production in the lungs, was eliminated in Itk(-/-) mice. Collectively, our data suggest a critical role of Itk in airway mast cell degranulation in vivo that together with an impaired T cell response prevents the development of both acute and late phase inflammatory allergic reactions.
Forssell
Johan
J
Transplantation Center, Foundation for Biomedical Research, Academy of Athens, Athens, Greece.
Sideras
Pascalis
P
Eriksson
Christina
C
Malm-Erjefält
Monika
M
Rydell-Törmänen
Kristina
K
Ericsson
Per-Olof
PO
Erjefält
Jonas S
JS
D000208:Acute Disease; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000276:immunology*; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism*; D008407:Mast Cells / Q000201:enzymology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; C080813:emt protein-tyrosine kinase