Published ahead of print on March 18, 2005, doi:10.1165/rcmb.2004-0348OC Am. J. Respir. Cell Mol. Biol., Volume 32, Number 6, June 2005, 511-520 A more recent version of this article appeared on June 1, 2005
Submitted on November 9, 2004 Interleukin-2 Inducible T Cell Kinase Regulates Mast Cell Degranulation and Acute Allergic ResponsesJohan Forssell1,1 Institute for Medical Sciences, Umea University, Umea, Sweden, 2 Transplantation Center, Foundation for Biomedical Research Academy of Athens, Athens, Greece; AstraZeneca R & D, Lund, Sweden, 3 AstraZeneca R & D, Lund, Sweden, 4 Department of Clinical and Experimental Pharmacology, Lund University, Lund, Sweden, 5 Department of Physiological Sciences, Lund University, Lund, Sweden * To whom correspondence should be addressed. E-mail: jonas.erjefalt{at}mphy.lu.se.
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-HSA 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.
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