Essential role of platelet-activating factor in control of Leishmania (Leishmania) amazonensis infection

In the present study we investigated the role of platelet-activating factor (PAF) and prostaglandins in experimental Leishmania (Leishmania) amazonens is infection and the relationship between these mediators and nitric oxide (NO) production. Mouse peritoneal macrophages elicited with thioglicolate w ere infected with leishmania amastigotes, and the infection index determine d 48 h later. The course of infection was monitored for 5 weeks in mice inf ected in the footpad with promastigotes by measuring the footpad swelling a nd parasite load in regional lymph nodes and spleen. The addition of PAF to C57BL/6 mouse macrophages significantly inhibited parasite growth and indu ced NO production. Treatment of macrophages with a selective PAF antagonist , WEB2086, increased the infection, indicating that endogenously produced P AF regulates macrophage ability to control leishmania infection. This effec t of PAF was abolished by addition of the inhibitor of NO synthesis, L-NAME , to the cultures. The addition of prostaglandin E, significantly increased the infection and NO production. Treatment with cyclo-oxygenase inhibitor, indomethacin, reduced the infection and PAF-induced release of NO. Thus, t he increased NO production induced by PAF seems to be mediated by prostagla ndins. The more-selective inhibitors of cyclo-oxygenase 2, nimesulide and N S-398, had no significant effect. Thus, antileishmanial activity correlates better with the presence of PAF or absence of prostaglandins than with NO production. In vivo treatment with PAF antagonists significantly increased leishmania lesions, as well as the parasite load, in regional lymph nodes a nd spleens. These findings indicate that PAF is essential for the control o f leishmania infection.