title: Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement.
abstract: Neutrophil chemotaxis is a critical component of the innate immune response. Neutrophils can sense an extremely shallow gradient of chemoattractants and produce relatively robust chemotactic behavior. This directional migration requires cell polarization with actin polymerization occurring predominantly in the leading edge. Synthesis of phosphatidylinositol (3,4,5) trisphosphate (PIP3) by phosphoinositide 3-kinase (PI3K) contributes to asymmetric F-actin synthesis and cell polarization during neutrophil chemotaxis. To determine the contribution of the hemopoietic cell-restricted PI3K delta in neutrophil chemotaxis, we have developed a potent and selective PI3K delta inhibitor, IC87114. IC87114 inhibited polarized morphology of neutrophils, fMLP-stimulated PIP3 production and chemotaxis. Tracking analysis of IC87114-treated neutrophils indicated that PI3K delta activity was required for the directional component of chemotaxis, but not for random movement. Inhibition of PI3K delta, however, did not block F-actin synthesis or neutrophil adhesion. These results demonstrate that PI3K delta can play a selective role in the amplification of PIP3 levels that lead to neutrophil polarization and directional migration.
authors.affiliation: ICOS Corporation, Bothell, WA 98021, USA. csadhu@icos.com
authors.forename: Chanchal
authors.initials: C
authors.lastname: Sadhu
authors.forename: Boris
authors.initials: B
authors.lastname: Masinovsky
authors.forename: Ken
authors.initials: K
authors.lastname: Dick
authors.forename: C Gregory
authors.initials: CG
authors.lastname: Sowell
authors.forename: Donald E
authors.initials: DE
authors.lastname: Staunton
mesh_terms: D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000096:biosynthesis; D000081082:Phosphoinositide-3 Kinase Inhibitors
chemical_list: D002867:Chromones; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009025:Morpholines; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; C060974:phosphatidylinositol 3,4,5-triphosphate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C486018:PIK3CD protein, human