Role for tyrosine phosphorylation and Lyn tyrosine kinase in fas receptor-mediated apoptosis in eosinophils.
Fas ligand/Fas receptor molecular interactions have been implicated as having an important function for the regulation of eosinophil apoptosis. The purpose of the present study was to investigate biochemical events triggered by the engagement of the Fas receptor in freshly isolated human and mouse eosinophils. Activation of the Fas receptor on eosinophils with the agonistic anti-Fas monoclonal antibody (MoAb) resulted in increased tyrosine phosphorylation of several intracellular proteins. The tyrosine kinase inhibitors lavendustin A and genistein inhibited Fas receptor-induced cell death in both human and mouse eosinophils in vitro and prevented, at least partially, Fas receptor-mediated resolution of eosinophilic inflammation in a mouse in vivo model of lung eosinophilia. In addition, in freshly purified human eosinophils, lavendustin A prevented anti-Fas MoAb-induced proteolytic cleavage of lamin B, suggesting that tyrosine kinases may amplify the proteolytic signaling cascade within interleukin-1beta converting enzyme (ICE) family proteases. Moreover, the tyrosine kinase Lyn was identified as being involved in Fas receptor-mediated cell death. Collectively, these results demonstrate that tyrosine phosphorylation is an important step in the generation of the Fas receptor-linked transmembrane death signal in eosinophils and that Lyn participates in this pathway.
Simon
H U
HU
Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland. hus@siaf.unizh.ch
Yousefi
S
S
Dibbert
B
B
Hebestreit
H
H
Weber
M
M
Branch
D R
DR
Blaser
K
K
Levi-Schaffer
F
F
Anderson
G P
GP
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000473:pathology* / Q000502:physiology; D053222:Fas Ligand Protein; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology / Q000502:physiology; D051379:Mice; D010636:Phenols / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019014:fas Receptor / Q000502:physiology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D010636:Phenols; D019014:fas Receptor; C062898:lavendustin A; D019833:Genistein; D019061:src-Family Kinases