Tissue- and stimulus-dependent role of phosphatidylinositol 3-kinase isoforms for neutrophil recruitment induced by chemoattractants in vivo.
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 PI3Kgamma and PI3Kdelta for neutrophil influx induced by the exogenous administration or the endogenous generation of the chemokine CXCL1. Administration of CXCL1 in PI3Kgamma(-/-) 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 PI3Kgamma(-/-) or WT mice. Neutrophil influx was not altered by treatment of WT mice with a specific PI3Kdelta inhibitor, IC87114, or a specific PI3Kgamma inhibitor, AS605240. The administration of IC87114 prevented CXCL1-induced neutrophil recruitment only in presence of the PI3Kgamma inhibitor or in PI3Kgamma(-/-) mice. Ag challenge of immunized mice induced CXCR2-dependent neutrophil recruitment that was inhibited by wortmannin or by blockade of and PI3Kdelta in PI3Kgamma(-/-) mice. Neutrophil recruitment to bronchoalveolar lavage induced by exogenously added or endogenous production of CXCL1 was prevented in PI3Kgamma(-/-) mice. The accumulation of the neutrophils in lung tissues was significantly inhibited only in PI3Kgamma(-/-) mice treated with IC87114. Neutrophil recruitment induced by exogenous administration of C5a or fMLP appeared to rely solely on PI3Kgamma. Altogether, our data demonstrate that there is a tissue- and stimulus-dependent role of PI3Kgamma and PI3Kdelta for neutrophil recruitment induced by different chemoattractants in vivo.
Pinho
Vanessa
V
Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil. vpinho@icb.ufmg.br
Russo
Remo Castro
RC
de Castro Russo
Remo
R
Amaral
Flávio A
FA
de Sousa
Lirlândia P
LP
Barsante
Michele M
MM
de Souza
Danielle G
DG
Alves-Filho
José C
JC
Cara
Denise C
DC
Hayflick
Joel S
JS
Rommel
Christian
C
Ruckle
Thomas
T
Rossi
Adriano G
AG
Teixeira
Mauro M
MM
D000818:Animals; D054360:Chemokine CXCL1 / Q000008:administration & dosage / Q000494:pharmacology*; D002630:Chemotactic Factors / Q000008:administration & dosage / Q000494:pharmacology*; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology; D058544:Class Ib Phosphatidylinositol 3-Kinase; D004195:Disease Models, Animal; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
D054360:Chemokine CXCL1; D002630:Chemotactic Factors; D007527:Isoenzymes; D011994:Recombinant Proteins; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse