title: A class IA PI3K controls inflammatory cytokine production in human neutrophils.
abstract: Neutrophils are generally the first leukocytes to arrive at sites of inflammation or injury, where they release a variety of inflammatory mediators, which contribute to shaping the ensuing immune response. Here, we show that in neutrophils exposed to physiological stimuli (i.e. LPS and TNF-α), inhibition of the PI3K signaling pathway impairs the synthesis and secretion of IL-8, Mip-1α, and Mip-1β. Further investigation showed that Mip-1α and Mip-1β gene transcription was similarly decreased, whereas IL-8 transcription and steady-state mRNA levels were unaffected. Accordingly, PI3K inhibition had no impact on NF-κB or C/EBP activation, which are essential for IL-8 transcription, but the basis for this selective inhibition of chemokine transcription remains elusive. We nevertheless identified translational targets of the PI3K pathway (S6, S6 kinase, 4E-BP1). Inhibitor studies and overexpression experiments further established that the various effects of PI3K on chemokine production can be ascribed to p85α and p110δ subunits. Finally, we show that in LPS- and TNF-activated neutrophils, PI3K acts downstream of the kinases p38 MAPK and TAK1. Given the importance of neutrophils and their products in numerous chronic inflammatory disorders, the PI3K pathway could represent an attractive therapeutic target.
authors.affiliation: Pulmonary Division, Faculty of Medicine, Université de Sherbrooke; and Centre de recherche du CHUS, Sherbrooke, QC, Canada.
authors.forename: Carl F
authors.initials: CF
authors.lastname: Fortin
authors.forename: Alexandre
authors.initials: A
authors.lastname: Cloutier
authors.forename: Thornin
authors.initials: T
authors.lastname: Ear
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Sylvain-Prévost
authors.forename: Thomas Z
authors.initials: TZ
authors.lastname: Mayer
authors.forename: Rim
authors.initials: R
authors.lastname: Bouchelaghem
authors.forename: Patrick P
authors.initials: PP
authors.lastname: McDonald
mesh_terms: D002461:Cell Line, Transformed; D002867:Chromones / Q000494:pharmacology; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D009025:Morpholines / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015025:Zearalenone / Q000031:analogs & derivatives / Q000494:pharmacology / Q000008:administration & dosage; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000099151:MAP Kinase Kinase Kinase 7; D007783:Lactones; D012118:Resorcinols
chemical_list: D002867:Chromones; D058543:Class Ia Phosphatidylinositol 3-Kinase; D016207:Cytokines; D007093:Imidazoles; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D015025:Zearalenone; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C505734:7-oxozeanol; D007783:Lactones; D012118:Resorcinols; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole