15-hydroxy-5-8-11-13-eicosatetraenoic-acid and artemisinin

Severe falciparum malaria is characterized by the sequestration of infected erythrocytes and leukocyte recruitment in the microvasculature, resulting in impaired blood flow and metabolic disturbances. Which parasite products cause chemokine production, thus contributing to the strong host inflammatory response and cellular recruitment are not well characterized. Here, we studied haemozoin (Hz), the end-product of haem, a ferriprotoporphyrin-IX crystal bound to host and parasite lipids, DNA, and proteins. We found that natural Hz isolated from Plasmodium falciparum cultures induces CXCL8 and CCL5 production in human dermal microvascular endothelial cells (HMEC-1) in a time-dependent manner. This up-regulation is not caused by haem but rather by Hz-generated lipoperoxidation products (15-HETE) and fibrinogen associated to Hz, and is, at least in part, triggered by the activation of NF-κB, as it was significantly inhibited by artemisinin and other NF-κB pathway inhibitors.

Topics: Animals; Antimalarials; Artemisinins; Cell Line; Chemokines; Endothelial Cells; Endothelium; Erythrocytes; Fibrinogen; Gene Expression Regulation; Hemeproteins; Humans; Hydroxyeicosatetraenoic Acids; Lipid Peroxidation; Plasmodium falciparum; Up-Regulation