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* Departamento de Bioquímica e Imunologia,
Departamento de Morfologia,
Departamento de Patologia, and
Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil;
¶ Departmento de Farmacologia, Escola de Medicina de Ribeirão Preto, Universidade de São Paulo, São Paulo, Brazil;
|| ICOS Corporation, Bothell, WA 98021;
# Merck Serono International, Geneva, Switzerland; and
** Medical Research Council Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
PI3K plays a fundamental role in regulating neutrophil recruitment into sites of inflammation but the role of the different isoforms of PI3K remains unclear. In this study, we evaluated the role of PI3K
and PI3K
for neutrophil influx induced by the exogenous administration or the endogenous generation of the chemokine CXCL1. Administration of CXCL1 in PI3K–/– or wild-type (WT) mice induced similar increases in leukocyte rolling, adhesion, and emigration in the cremaster muscle when examined by intravital microscopy. The induction of neutrophil recruitment into the pleural cavity or the tibia-femoral joint induced by the injection of CXCL1 was not significantly different in PI3K–/– or WT mice. Neutrophil influx was not altered by treatment of WT mice with a specific PI3K inhibitor, IC87114, or a specific PI3K inhibitor, AS605240. The administration of IC87114 prevented CXCL1-induced neutrophil recruitment only in presence of the PI3K inhibitor or in PI3K–/– mice. Ag challenge of immunized mice induced CXCR2-dependent neutrophil recruitment that was inhibited by wortmannin or by blockade of and PI3K in PI3K–/– mice. Neutrophil recruitment to bronchoalveolar lavage induced by exogenously added or endogenous production of CXCL1 was prevented in PI3K–/– mice. The accumulation of the neutrophils in lung tissues was significantly inhibited only in PI3K–/– mice treated with IC87114. Neutrophil recruitment induced by exogenous administration of C5a or fMLP appeared to rely solely on PI3K. Altogether, our data demonstrate that there is a tissue- and stimulus-dependent role of PI3K and PI3K for neutrophil recruitment induced by different chemoattractants in vivo.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (Brazil), Fundação de Amparo a Pesquisas do Estado de Minas Gerais (Brazil).
2 Address correspondence and reprint requests to Dr. Vanessa Pinho, Imunofarmacologia, Departamento de Bioquímica e Imunologia, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Avenida Antonio Carlos, 6627 Pampulha, 31270-901, Belo Horizonte, MG, Brazil. E-mail address: vpinho{at}icb.ufmg.br
3 Abbreviations used in this paper: PtdIns, phosphatidylinositol; GPCR, G protein-coupled receptor; WT, wild type; i.pl., intrapleural; BAL, bronchoalveolar lavage; MPO, myeloperoxidase.
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