Tyrosine kinases are required for interferon-gamma-stimulated proliferation of Trypanosoma brucei brucei.
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.
Mustafa
E
E
Division of Neurology, Huddinge University Hospital, Stockholm, Sweden.
Bakhiet
M
M
Jaster
R
R
Bittorf
T
T
Mix
E
E
Olsson
T
T
D000818:Animals; D002109:Caffeic Acids / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins; D014346:Trypanosoma brucei brucei / Q000254:growth & development*; D014353:Trypanosomiasis, African / Q000201:enzymology / Q000469:parasitology; D020032:Tyrphostins
D002109:Caffeic Acids; D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D011994:Recombinant Proteins; D020032:Tyrphostins; C060152:tyrphostin 47; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases