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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-03-0979.
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Blood, 15 January 2003, Vol. 101, No. 2, pp. 722-728
PHAGOCYTES
Malaria-parasitized erythrocytes and hemozoin nonenzymatically
generate large amounts of hydroxy fatty acids that inhibit monocyte
functions
Evelin Schwarzer,
Hartmut Kühn,
Elena Valente, and
Paolo Arese
From the Institute of Biochemistry, Humboldt
University-Charité, Berlin, Germany; and the
Department of Genetics, Biology and Biochemistry, University of Torino
Medical School, Torino, Italy
Plasmodium falciparum digests up to 75% of
erythrocyte (red blood cell [RBC]) hemoglobin and forms
hemozoin. Phagocytosed hemozoin and trophozoites inhibit important
monocyte functions. Delipidized trophozoites and hemozoin were
remarkably less toxic to monocytes. Parasitized RBCs and hemozoin
contained large amounts of mostly esterified monohydroxy derivatives
(OH-PUFAs), the stable end products of peroxidation of polyenoic fatty
acids. The concentrations of OH-PUFA were 1.8 micromoles per liter RBCs
in nonparasitized RBCs, 11.1 micromoles per liter RBCs in rings, 35 micromoles per liter RBCs in trophozoites; and approximately 90 micromoles per liter RBC equivalents in hemozoin. In
parasitized RBCs and hemozoin a complex mixture of monohydroxy
derivatives of arachidonic (HETEs) and linoleic (HODEs) acid was
determined. Respectively, 13- and 9-HODE and 9- and 12-HETE were
predominant in hemozoin and parasitized RBCs. The estimated
concentrations of all HETE isomers were 33 and 39 micromoles per liter
RBCs or RBC equivalents in trophozoites and hemozoin, respectively. No
evidence of lipoxygenase activity was found, whereas the large number
of positional and optical isomers, the racemic structure, and their
generation by incubation of arachidonic acid with hemozoin indicated
nonenzymatic origin via heme-catalysis. Sub/low micromolar
concentrations of 12- and 15-HETE were toxic to monocytes, whereas HODE
isomers were ineffective. Low micromolar concentrations of HETE isomers
were estimated to be similarly present in monocytes after phagocytosis
of trophozoites or hemozoin. Thus, specific products of heme-catalyzed
lipid peroxidation appear to contribute to hemozoin toxicity to
phagocytes and may thus play a role in increased cytoadherence,
vascular permeability, and chemotaxis, as well as in immunodepression
in malaria.
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