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

Abstract

The tyrosine kinase activity of Trypanosoma brucei brucei upon stimulation with interferon-γ (IFN-γ) was investigated. IFN-γ 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-γ-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-γ-stimulated trypanosomes. In animals, 2x 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-γ-stimulated T. b. brucei, and specific tyrosine kinase inhibitors can prevent trypanosome growth in vitro and in vivo.