L-arginine-dependent Destruction of Intrahepatic Malaria Parasites in Response to Tumor Necrosis Factor And/or Interleukin 6 Stimulation

There is growing evidence that cytokines (interleukin [IL] 1, IL 6, interferon-gamma, tumor necrosis factor [TNF]) directly or indirectly interfere with the intrahepatic development of malaria parasites. Recent work in our laboratory clearly showed that TNF can affect the hepatic development of parasites via IL 6 secreted by liver nonparenchymal cells. The possible participation of an L-arginine-dependent effector mechanism has been studied to explain the TNF/IL 6-induced inhibition. We thus investigated if NGmonomethyl-L-arginine and N omega-nitro-L-arginine, two specific inhibitors of inorganic nitrogen oxide synthesis from L-arginine, were able to affect the inhibitory effect of TNF and/or IL 6 in co-cultures. At 0.1 and 0.5 mM both L-arginine analogues reversed the inhibitory effect of these cytokines. An interesting observation is that L-arginine analogues enhance schizont development in the absence of prior cytokine contact. This result indicates an hepatic basal L-arginine-dependent anti-parasitic activity which might explain the existence of self-degenerating hepatic forms as previously reported.