Inhibition of Pyk2 blocks airway inflammation and hyperresponsiveness in a mouse model of asthma.
The objective of this investigation was to determine the role of Pyk2, an intracellular nonreceptor protein tyrosine kinase for postadhesive inflammatory cell migration, on airway inflammation and hyperresponsiveness in immune-sensitized mice. Blockade of Pyk2 was effected by intraperitoneal administration of dominant-negative C-terminal Pyk2 fused to a TAT protein transduction domain (TAT-Pyk2-CT). Ovalbumin challenge elicited infiltration of both eosinophils and lymphocytes into airways, increased mucus-containing epithelial cells, and caused increased airway hyperresponsiveness to methacholine in immune-sensitized mice. Pretreatment with 10 mg/kg TAT-Pyk2-CT intraperitoneally blocked all of these effects and further decreased secretion of Th2 cytokine IL-4, IL-5, and IL-13 into the bronchoalveolar lavage fluid. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by systemic pretreatment with TAT-Pyk2-CT. In each paradigm, treatment with control protein TAT-GFP had no blocking effect. We conclude that Pyk2, which is essential for inflammatory cell migration in vitro, regulates airway inflammation, Th2 cytokine secretion, and airway hyperresponsiveness in the ovalbumin-sensitized mice during antigen challenge in vivo.
Duan
Yingli
Y
Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Learoyd
Jonathan
J
Meliton
Angelo Y
AY
Clay
Bryan S
BS
Leff
Alan R
AR
Zhu
Xiangdong
X
D000818:Animals; D000941:Antigens / Q000009:adverse effects / Q000494:pharmacology; D001249:Asthma / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D004804:Eosinophils / Q000378:metabolism* / Q000473:pathology; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D018418:Th2 Cells / Q000378:metabolism* / Q000473:pathology
D000941:Antigens; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse