Effect of tyrosine kinase inhibitors on the STAT6 signaling of host ARPE-19 cells infected with Toxoplasma gondii

초록

The spontaneous ST AT6 phosphorylation and the following specific gene expressions of host cells are major strategy for the survival of the protozoan intacellular parasite Toxoplasma gondii against the parasiticidal events through the ST AT1 phosphorylation by the interferon-gamma provoked in the infection. Several tyrosine kinase inhibitors(TKI) are tested the effect on the growth inhibition of intracellular growth of T. gondii and the relationship with ST AT1 and 6 phosphorylation in the retinal cell line, ARPE-19. Among the tested TKIs, Afatinib (pan ErbB/EGFR inhibitor, 5mM) inhibits the growth of T. gondii of 98.0%, which is comparable to pyrimethamine (5mM) of 96.9%, and followed by Erlotinib (ErbB1/EGFR inhibitor, 20 mM) of 33.8% and Sunitinib (PDGFR or c-Kit inhibitor, 10 mM) of 21.3% in the counting the number of T. gondii per parasitophorous vacuolar membrane within host cells at 12-hour interval for 72 hr. In the early stage of infection(2, 4, and 8 hr after T. gondii challenge), Afatinib inhibits the spontaneous phosphorylation of ST AT6 in western blot and immunofluorescence assay, but still the ST AT1 phosphorylation is not affected by interferon-gamma stimulation. On the while, Jak1/Jak3, the upper hierarchical kinase of the cytokine signaling, are strongly phosphorylated at 2 hr and then disappear entirely after 4 hr. These suggest the tyrosine kinase inhibitors, belonging to a kind of anti-cancer drug, might play an important role in inhibition of intracellular replication of T. gondii.through the inhibition of direct phosphorylation of ST AT6 by T. gondii.