TYROSINE KINASES ARE REQUIRED FOR INTERFERON-GAMMA-STIMULATED PROLIFERATION OF TRYPANOSOMA-BRUCEI-BRUCEI

The tyrosine kinase activity of Trypanosoma brucei brucei upon stimula tion with interferon-gamma (IFN-gamma) was investigated. IFN-gamma ind uced a rapid and strong increase of tyrosine phosphorylation of severa l cellular proteins that reached maximum after 5 min and was followed by a decrease to control levels after 120 min. The tyrosine kinase-spe cific 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 [H-3]thymidine uptake by IFN-gamma-stimulated trypanosome s. In animals, 2 x 0.5 mg of tyrphostin A47 (injected intraperitoneall y) 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-s timulated T. b. brucei, and specific tyrosine kinase inhibitors can pr event trypanosome growth in vitro and in vivo.