Src-family kinase-p53/ Lyn p56 plays an important role in TNF-alpha-stimulated production of O2- by human neutrophils adherent to fibrinogen.
Stimulation of neutrophil function by TNFalpha is largely dependent on beta2 integrins. It has also been proposed that src-family kinases are involved in this process. However, the functions of src-like kinases in human neutrophils still remain to be determined. In the present study, we used the new src-family kinase specific inhibitor PP1 [4-Amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] to investigate the role src-kinases play in TNFalpha stimulation of neutrophil function. Our results demonstrated that, in neutrophils adherent to fibrinogen, PP1 inhibited TNFalpha-stimulated superoxide production and protein tyrosine phosphorylation in a dose-dependent manner. In in vitro kinase assays, PP1 profoundly inhibited the activation of p53/56lyn but not p59hck or p72syk. Only slight inhibition was found of p58c-fgr. These data indicate that p53/56lyn plays an important role in TNFalpha-mediated stimulation of PMN function.
Yan
S R
SR
Department of Periodontics, University of Pittsburgh School of Dental Medicine, Pennsylvania 15261, USA.
Novak
M J
MJ
D005340:Fibrinogen / Q000378:metabolism*; D006801:Humans; D009504:Neutrophils / Q000201:enzymology* / Q000378:metabolism; D009856:Oncogene Proteins, Viral; D010100:Oxygen / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D009856:Oncogene Proteins, Viral; D011720:Pyrazoles; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D005340:Fibrinogen; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D010100:Oxygen