TNFalpha elicits association of PI 3-kinase with the p60TNFR and activation of PI 3-kinase in adherent neutrophils.
Tumor necrosis factor (TNFalpha) is an incomplete secretagogue in neutrophils and requires the engagement of beta integrins to trigger secretion of superoxide anion (O(-)(2)). The p60 TNF receptor (p60TNFR) is responsible for signal transduction for activation of O(-)(2) generation. Activation of TNFalpha-triggered O(-)(2) generation in neutrophils adherent to fibrinogen-coated surfaces involves the beta2 integrin receptor CD11b/CD18. Phosphoinositide 3-kinase (PI 3-kinase) is essential for activation of O(-)(2) generation; wortmannin, an inhibitor of PI 3-kinase, inhibited TNFalpha-elicited O(-)(2) generation. p60TNFR immunoprecipitated from neutrophils was associated with immunoreactivity to PI 3-kinase in adherent neutrophils exposed to TNFalpha, but not in TNFalpha-treated neutrophils in suspension. In addition, PI 3-kinase immunoprecipitated from TNFalpha-activated neutrophils showed enhanced activity in adherent but not in nonadherent neutrophils. These findings suggest that synergism between CD11b/CD18 and p60TNFR in the presence of TNFalpha is required to elicit assembly of a signaling complex involving association of p60TNFR with PI 3-kinase, activation of PI 3-kinase, and generation of O(-)(2).
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, 19104, USA.
H M
HM
Korchak
L E
LE
Kilpatrick
D002448:Cell Adhesion; D004789:Enzyme Activation; D007700:Kinetics; D009504:Neutrophils / Q000166:cytology / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases