Tyrosine kinases are required for interferon-gamma-stimulated proliferation of Trypanosoma brucei brucei.

Abstract

The tyrosine kinase activity of Trypanosoma brucei brucei upon stimulation with interferon-gamma (IFN-gamma) was investigated. IFN-gamma induced a rapid and strong increase of tyrosine phosphorylation of several cellular proteins that reached maximum after 5 min and was followed by a decrease to control levels after 120 min. The tyrosine kinase-specific inhibitor tyrphostin A47 at a concentration of 10(-6) M reduced IFN-gamma-induced protein phosphorylation. In vitro application of 10(-6) M tyrphostin A47 to the trypanosome cultures caused a significant reduction of [3H]thymidine uptake by IFN-gamma-stimulated trypanosomes. In animals, 2 x 0.5 mg of tyrphostin A47 (injected intraperitoneally) caused a significant reduction of parasite growth compared with the vehicle dimethyl sulfoxide or the inactive compound tyrphostin A1. In conclusion, tyrosine kinases are strongly up-regulated in IFN-gamma-stimulated T. b. brucei, and specific tyrosine kinase inhibitors can prevent trypanosome growth in vitro and in vivo.