The Journal of Experimental Medicine
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Published 17 November 2003. doi:10.1084/jem.20030298
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© Rockefeller University Press, 0022-1007/2003/11/1573 $5.00
The Journal of Experimental Medicine, Volume 198, Number 10, 1573-1582

Blockade of Inflammation and Airway Hyperresponsiveness in Immune-sensitized Mice by Dominant-Negative Phosphoinositide 3-Kinase–TAT

Shigeharu Myou1, Alan R. Leff1,2, Saori Myo1, Evan Boetticher1, Jiankun Tong1, Angelo Y. Meliton1, Jie Liu1, Nilda M. Munoz1 and Xiangdong Zhu1

1 Section of Pulmonary and Critical Care Medicine, Department of Medicine
2 Department of Neurobiology, Pharmacology, and Physiology, and Committees on Molecular Medicine, Clinical Pharmacology, and Cell Physiology, University of Chicago, Chicago, IL 60637

Address correspondence to Dr. Alan R. Leff, Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637. Phone: (773) 702-1859; Fax: (773) 702-9181; email: aleff{at}medicine.bsd.uchicago.edu

Phosphoinositide 3-kinase (PI3K) is thought to contribute to the pathogenesis of asthma by effecting the recruitment, activation, and apoptosis of inflammatory cells. We examined the role of class IA PI3K in antigen-induced airway inflammation and hyperresponsiveness by i.p. administration into mice of {Delta}p85 protein, a dominant negative form of the class IA PI3K regulatory subunit, p85{alpha}, which was fused to HIV-TAT (TAT-{Delta}p85). Intraperitoneal administration of TAT-{Delta}p85 caused time-dependent transduction into blood leukocytes, and inhibited activated phosphorylation of protein kinase B (PKB), a downstream target of PI3K, in lung tissues in mice receiving intranasal FMLP. Antigen challenge elicited pulmonary infiltration of lymphocytes, eosinophils and neutrophils, increase in mucus-containing epithelial cells, and airway hyperresponsiveness to methacholine. Except for modest airway neutrophilia, these effects all were blocked by treatment with 3–10 mg/kg of TAT-{Delta}p85. There was also significant reduction in IL-5 and IL-4 secretion into the BAL. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by systemic pretreatment with TAT-{Delta}p85. We conclude that PI3K has a regulatory role in Th2-cell cytokine secretion, airway inflammation, and airway hyperresponsiveness in mice.

Key Words: allergy • cytokines • eosinophils • lung • inflammation


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