Blockade of inflammation and airway hyperresponsiveness in immune-sensitized mice by dominant-negative phosphoinositide 3-kinase-TAT.
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 Deltap85 protein, a dominant negative form of the class IA PI3K regulatory subunit, p85alpha, which was fused to HIV-TAT (TAT-Deltap85). Intraperitoneal administration of TAT-Deltap85 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-Deltap85. 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-Deltap85. We conclude that PI3K has a regulatory role in Th2-cell cytokine secretion, airway inflammation, and airway hyperresponsiveness in mice.
Myou
Shigeharu
S
Section of Pulmonary and Critical Care Medicine, Department of Medicine, The University of Chicago, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Leff
Alan R
AR
Myo
Saori
S
Boetticher
Evan
E
Tong
Jiankun
J
Meliton
Angelo Y
AY
Liu
Jie
J
Munoz
Nilda M
NM
Zhu
Xiangdong
X
D000818:Animals; D006967:Hypersensitivity / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D012140:Respiratory Tract Diseases / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control
D015848:Interleukin-5; D019869:Phosphatidylinositol 3-Kinases