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Agonistic effects of tyrphostins on human peripheral mononuclear cells
H M Lander1, D M Levine, A Novogrodsky
1Rogosin Institute, New York, New York.
Abstract:
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.
Insights
Tyrphostins, inhibitors of protein tyrosine kinases, show dual effects on human immune cells. These compounds can stimulate or inhibit lymphocyte functions, suggesting potential therapeutic applications.
Area of Science:
- Immunology
- Biochemistry
- Pharmacology
Background:
- Src family tyrosine kinases (p56lck, p59fyn) are crucial for T-cell receptor signaling.
- These kinases are regulated by phosphorylation of a C-terminal tyrosine residue.
- Tyrphostins are synthetic compounds that selectively inhibit protein tyrosine kinases.
Purpose of the Study:
- To investigate the agonistic and antagonistic effects of various tyrphostins on human peripheral blood mononuclear cells (PBM).
- To explore the impact of tyrphostins on glucose uptake, IL-2-induced cytotoxicity, [3H]thymidine incorporation, and cytokine secretion in PBM.
Main Methods:
- Treatment of human PBM with different concentrations of tyrphostins (AG126, AG183, AG17).
- Assessment of glucose uptake, IL-2-induced cytotoxicity, and [3H]thymidine incorporation.
- Measurement of cytokine secretion (TNF-alpha, IFN-gamma, IL-1, IL-6) with or without costimulation.
Main Results:
- Low concentrations of tyrphostins enhanced glucose uptake in PBM.
- AG126 and AG183 showed biphasic enhancement of IL-2-induced cytotoxicity, while AG17 inhibited it.
- Tyrphostins differentially affected [3H]thymidine incorporation; AG17 was the most potent inhibitor.
- AG126 and AG183 enhanced TNF-alpha secretion, particularly with IL-2.
- AG126 also boosted IFN-gamma, IL-1, and IL-6 production under stress conditions.
Conclusions:
- Tyrphostins exhibit complex, concentration-dependent effects on PBM functions, including glucose metabolism, cytotoxicity, proliferation, and cytokine release.
- The observed stimulatory and inhibitory effects on lymphocyte functions suggest potential therapeutic utility for tyrphostins.