Blockade of Class IA Phosphoinositide 3-Kinase in Neutrophils Prevents NADPH Oxidase Activation- and Adhesion-dependent Inflammation
| Autor: | Xiangdong Zhu, Jian Fu, Asrar B. Malik, Randall S. Frey, Qinghui Liu, Xiao Pei Gao |
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| Rok vydání: | 2007 |
| Předmět: |
Lung Diseases
Neutrophils Macrophage-1 Antigen Vascular permeability CD18 Biochemistry Mice Phosphatidylinositol 3-Kinases chemistry.chemical_compound Multienzyme Complexes Superoxides Cell Adhesion Animals NADH NADPH Oxidoreductases Cell adhesion Lung Molecular Biology Phosphoinositide-3 Kinase Inhibitors Inflammation Phosphoinositide 3-kinase NADPH oxidase biology Tumor Necrosis Factor-alpha Superoxide hemic and immune systems Cell Biology Molecular biology Enzyme Activation chemistry Integrin alpha M biology.protein Phosphorylation |
| Zdroj: | Journal of Biological Chemistry. 282:6116-6125 |
| ISSN: | 0021-9258 |
| Popis: | We examined the role of class IA phosphoinositide 3-kinase (PI3K) in the regulation of activation of NADPH oxidase in PMNs and the mechanism of PMN-dependent lung inflammation and microvessel injury induced by the pro-inflammatory cytokine TNF-alpha. TNF-alpha stimulation of PMNs resulted in superoxide production that was dependent on CD11b/CD18-mediated PMN adhesion. Additionally, TNF-alpha induced the association of CD11b/CD18 with the NADPH oxidase subunit Nox2 (gp91(phox)) and phosphorylation of p47(phox), indicating the CD11b/CD18 dependence of NADPH oxidase activation. Transduction of wild-type PMNs with Deltap85 protein, a dominant-negative form of the class IA PI3K regulatory subunit, p85alpha, fused to HIV-TAT (TAT-Deltap85) prevented (i) CD11b/CD18-dependent PMN adhesion, (ii) interaction of CD11b/CD18 with Nox2 and phosphorylation of p47(phox), and (iii) PMN oxidant production. Furthermore, studies in mice showed that i.v. infusion of TAT-Deltap85 significantly reduced the recruitment of PMNs in lungs and increase in lung microvascular permeability induced by TNF-alpha. We conclude that class IA PI3K serves as a nodal point regulating CD11b/CD18-integrin-dependent PMN adhesion and activation of NADPH oxidase, and leads to oxidant production at sites of PMN adhesion, and the resultant lung microvascular injury in mice. |
| Databáze: | OpenAIRE |
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