THE HEME MOIETY OF MALARIA PIGMENT (BETA-HEMATIN) MEDIATES THE INHIBITION OF NITRIC-OXIDE AND TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION BY LIPOPOLYSACCHARIDE-STIMULATED MACROPHAGES

To investigate the effect of the heme moiety of malaria pigment, hemoz oin, on phagocyte functions, mouse macrophages were fed with insoluble beta-hematin, the synthetic heme-polymer chemically identical to the native pigment, or the soluble monomer, hematin. Production of inflamm atory cytokines, interleukin 1 (IL1), tumor necrosis factor alpha (TNF alpha), and nitric oxide (NO) was assayed in the supernatants after s timulation with lipopolysaccharide. The results indicate that both bet a-hematin and hematin induce a dose-dependent inhibition of macrophage production of TNF alpha and NO, but not of IL1. One-hour pretreatment with soluble hematin inhibited production of cytotoxic mediators by m ore than 50% compared to controls, while 6-hr exposure was necessary f or insoluble beta-hematin to induce the same level of inhibition. Howe ver, the same treatment did not modify the production of TNF alpha and NO by mouse microglia cell lines. The inhibition was partially counte rbalanced by adding sulphydryl group donors such as 2-mercaptoethanol, glutathione, or N-acetyl-cysteine during the preincubation time. The results of the present study confirm the inhibitory role of malaria pi gment and show that such effect is due to the heme moiety and may be s elective for the production of cytotoxic mediators by specific phagocy tes. The implications of these findings in the control of malaria infe ction and disease and in the pathogenesis of severe malaria are discus sed. (C) 1995 Academic Press. Inc.