title: Cyclooxygenase-2 deficiency in macrophages leads to defective p110γ PI3K signaling and impairs cell adhesion and migration.
abstract: Cyclooxygenase (Cox)-2 dependent PGs modulate several functions in many pathophysiological processes, including migration of immune cells. In this study, we addressed the role of Cox-2 in macrophage migration by using in vivo and in vitro models. Upon thioglycolate challenge, CD11b(+) F4/80(+) macrophages showed a diminished ability to migrate to the peritoneal cavity in cox-2(-/-) mice. In vivo migration of cox-2(-/-) macrophages from the peritoneal cavity to lymph nodes, as well as cell adhesion to the mesothelium, was reduced in response to LPS. In vitro migration of cox-2(-/-) macrophages toward MCP-1, RANTES, MIP-1α, or MIP-1β, as well as cell adhesion to ICAM-1 or fibronectin, was impaired. Defects in cell migration were not due to changes in chemokine receptor expression. Remarkably, cox-2(-/-) macrophages showed a deficiency in focal adhesion formation, with reduced phosphorylation of paxillin (Tyr(188)). Interestingly, expression of the p110γ catalytic subunit of PI3K was severely reduced in the absence of Cox-2, leading to defective Akt phosphorylation, as well as cdc42 and Rac-1 activation. Our results indicate that the paxillin/p110γ-PI3K/Cdc42/Rac1 axis is defective in cox-2(-/-) macrophages, which results in impaired cell adhesion and migration.
authors.affiliation: Departamento de Biología Molecular, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Díaz-Muñoz
authors.forename: Inés C
authors.initials: IC
authors.lastname: Osma-García
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Iñiguez
authors.forename: Manuel
authors.initials: M
authors.lastname: Fresno
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology; D002464:Cell Migration Inhibition / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000172:deficiency* / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D017737:Macrophages, Peritoneal / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018448:Models, Immunological; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D020764:cdc42 GTP-Binding Protein / Q000172:deficiency; D020830:rac1 GTP-Binding Protein / Q000172:deficiency
chemical_list: D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein