Agonistic effects of tyrphostins on human peripheral mononuclear cells.
Tyrosine kinases of the src family, p56lck and p59fyn, were implicated in the transduction of signals via the T-cell receptor complex. These kinases are negatively regulated by phosphorylation of a carboxyl-terminal tyrosine residue. Tyrphostins are synthetic low molecular weight compounds that selectively inhibit different protein tyrosine kinases. We report here on the agonistic and antagonistic effects of tyrphostins on human peripheral blood mononuclear cells (PBM). At low concentration, the tyrphostins enhanced glucose uptake and maximal stimulation was attained at a concentration characteristic for each of the tyrphostins used. Higher concentrations were less effective. The tyrphostins AG126 and AG183 were also found to enhance IL-2-induced cytotoxicity in human PBM in a biphasic manner. In contrast, the tyrphostin AG17 markedly inhibited IL-2-induced cytotoxicity at low AG17 concentration and no stimulation was observed. The tyrphostins tested had selective effects on [3H]thymidine incorporation induced by the mixed lymphocyte culture and different agents. The most potent inhibitor was AG17. Tyrphostins also affect cytokine secretion by human PBM. AG126 and AG183 enhanced TNF-alpha secretion and this effect was more prominent in the presence of IL-2. AG126 enhanced IFN-gamma, IL-1, and IL-6 production in PBM that were costimulated with the stress stimuli heat shock and phenylarsine oxide. The stimulatory effects of the tyrphostins on cytokine secretion and induction of cytotoxicity might be interrelated. The agonistic and antagonistic effects of tyrphostins on lymphocyte functions may have therapeutic potential.
Lander
H M
HM
Rogosin Institute, New York, New York.
Levine
D M
DM
Novogrodsky
A
A
D001597:Benzylidene Compounds / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003208:Concanavalin A; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D010835:Phytohemagglutinins / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013936:Thymidine / Q000378:metabolism; D020032:Tyrphostins
D001597:Benzylidene Compounds; D007376:Interleukin-2; D009570:Nitriles; D010636:Phenols; D010835:Phytohemagglutinins; D020032:Tyrphostins; D003208:Concanavalin A; C069028:AG 127; C069029:AG 183; D011505:Protein-Tyrosine Kinases; D005947:Glucose; D013936:Thymidine