Mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue.
The phosphoinositide 3-kinase (PI3K) catalytic subunit p110 delta is expressed in neutrophils and is thought to play a role in their accumulation at sites of inflammation by contributing to chemoattractant-directed migration. We report here that p110 delta is present in endothelial cells and participates in neutrophil trafficking by modulating the proadhesive state of these cells in response to tumor necrosis factor alpha (TNF alpha). Specifically, administration of the selective inhibitor of PI3K delta, IC87114, to animals reduced neutrophil tethering to and increased rolling velocities on cytokine-activated microvessels in a manner similar to that observed in mice deficient in p110 delta. These results were confirmed in vitro as inhibition of this isoform in endothelium, but not neutrophils, diminished cell attachment in flow. A role for PI3K delta in TNF alpha-induced signaling is demonstrated by a reduction in Akt-phosphorylation and phosphatidylinositol-dependent kinase 1 (PDK1) enzyme activity upon treatment of this cell type with IC87114. p110 delta expressed in neutrophils also contributes to trafficking as demonstrated by the impaired movement of these cells across inflamed venules in animals in which this catalytic subunit was blocked or genetically deleted, results corroborated in transwell migration assays. Thus, PI3K delta may be a reasonable therapeutic target in specific inflammatory conditions as blockade of its activity reduces neutrophil influx into tissues by diminishing their attachment to and migration across vascular endothelium.
Puri
Kamal D
KD
ICOS, Bothell, WA 98021, USA. kpuri@icos.com
Doggett
Teresa A
TA
Douangpanya
Jason
J
Hou
Yonghao
Y
Tino
William T
WT
Wilson
Tim
T
Graf
Thomas
T
Clayton
Elizabeth
E
Turner
Martin
M
Hayflick
Joel S
JS
Diacovo
Thomas G
TG
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D058534:Class I Phosphatidylinositol 3-Kinases; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D018715:Microscopy, Video; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D064413:3-Phosphoinositide-Dependent Protein Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; C421683:Pik3cd protein, mouse; C578564:Pdpk1 protein, mouse