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The Journal of Immunology, 2003, 171: 4379-4384.
Copyright © 2003 by The American Association of Immunologists

Blockade of Airway Inflammation and Hyperresponsiveness by HIV-TAT-Dominant Negative Ras 1

Shigeharu Myou2,*, Xiangdong Zhu2,*, Saori Myo*, Evan Boetticher*, Angelo Y. Meliton*, Jie Liu*, Nilda M. Munoz* and Alan R. Leff3,*,{dagger}

* Section of Pulmonary and Critical Care Medicine, Department of Medicine, and {dagger} Department of Neurobiology Pharmacology and Physiology and Committees on Molecular Medicine, Clinical Pharmacology, and Cell Physiology, University of Chicago, Chicago, IL 60637

We have reported previously that HIV-TAT-dominant negative (dn) Ras inhibits eosinophil adhesion to ICAM-1 after activation by IL-5 and eotaxin. In this study, we evaluated the role of Ras in Ag-induced airway inflammation and hyperresponsiveness by i.p. administration into mice of dnRas, which was fused to an HIV-TAT protein transduction domain (TAT-dnRas). Uptake of TAT-dnRas (t1/2 = 12 h) was demonstrated in leukocytes after i.p. administration. OVA-sensitization significantly increased eosinophil and lymphocyte numbers in bronchoalveolar lavage fluid 24 h after final challenge. Treatment of animals with 3–10 mg/kg TAT-dnRas blocked the migration of eosinophils from 464 ± 91 x 103/ml to 288 ± 79 x 103/ml with 3 mg/kg of TAT-dnRas (p < 0.05), and further decreased to 116 ± 63 x 103/ml after 10 mg/kg TAT-dnRas (p < 0.01). Histological examination demonstrated that inflammatory cell infiltration (largely eosinophils and mononuclear cells) and mucin production around the airways caused by OVA were blocked by TAT-dnRas. OVA challenge also caused airway hyperresponsiveness to methacholine, which was dose dependently blocked by treatment with TAT-dnRas. TAT-dnRas also blocked Ag-induced IL-4 and IL-5, but not IFN-{gamma}, production in lung tissue. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by pretreatment with TAT-dnRas. By contrast, TAT-green fluorescent protein or dnRas lacking the TAT protein transduction domain did not block airway inflammation, cytokine production, or airway hyperresponsiveness. We conclude that Ras mediates Th2 cytokine production, airway inflammation, and airway hyperresponsiveness in immune-sensitized mice.




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