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J. Exp. Med., Volume 188, Number 6, September 21, 1998 1197-1202

Plasmodium falciparum Produces Prostaglandins that are Pyrogenic, Somnogenic, and Immunosuppressive Substances in Humans

By B. Kilunga Kubata,* Naomi Eguchi,Dagger Yoshihiro Urade,* Kouwa Yamashita,§ Toshihide Mitamura,parallel Kumiko Tai,parallel Osamu Hayaishi,* and Toshihiro Horiiparallel

From the * Department of Molecular Behavioral Biology, Osaka Bioscience Institute, Furuedai, Suita, Osaka 565, Japan; Dagger  PRESTO, Japan Science and Technology Corporation, Furuedai, Suita, Osaka 565, Japan; § R&D Division, Pharmaceuticals Group, Nippon Kayaku Co., Ltd. Shimo, Kita-ku, Tokyo 115, Japan; and the parallel  Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565, Japan

Plasmodium falciparum causes the most severe form of human malaria, which kills ~1.5-2.7 million people every year, but the molecular mechanisms underlying the clinical symptoms and the host-parasite interaction remain unclear. We show here that P. falciparum produces prostaglandins (PGs) D2, E2, and F2alpha . After incubation with 1 mM arachidonic acid (AA), cell homogenates of P. falciparum produced PGs as determined by enzyme immunoassay and gas chromatography-selected ion monitoring. PG production in the parasite homogenate was not affected by the nonsteroidal antiinflammatory drugs aspirin and indomethacin, and was partially heat resistant, whereas PG biosynthesis by mammalian cyclooxygenase was completely inhibited by these chemicals and by heat treatment. Addition of AA to the parasite cell culture markedly increased an ability of the parasite cell homogenate to produce PGs and of parasitized red blood cells to accumulate PGs in the culture medium. PGD2 and PGE2 accumulated in the culture medium at the stages of trophozoites and schizonts more actively than at the ring stage. These findings are the first evidence of the direct involvement of a malaria parasite in the generation of substances that are pyrogenic and injurious to the host defenses. We will discuss a possible contribution of the parasite-produced PGs to pathogenesis and host-parasite interaction of P. falciparum.

Key words: Plasmodium falciparum;  prostaglandin;  malaria pathogenesis;  tumor necrosis factor alpha ;  pyrogen


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