DOCOSAHEXAENOIC ACID, A CONSTITUENT OF FETAL AND NEONATAL SERUM, INHIBITS NITRIC-OXIDE PRODUCTION BY MURINE MACROPHAGES STIMULATED BY IFN-GAMMA PLUS LPS, OR BY IFN-GAMMA PLUS LISTERIA-MONOCYTOGENES

Murine macrophage activation is deficient in the fetus and the neonate , and in areas of the placenta perfused by the fetal circulation. Feta l and neonatal serum concentrations of docosahexaenoic acid (DHA) are 150 mu M, or approximate to 50-fold higher than in the adult. We previ ously showed that DHA inhibits activation of the gene for inducible ni tric oxide synthase (iNOS) in murine macrophages stimulated in vitro w ith interferon gamma (IFN gamma) plus lipopolysaccharide (LPS). We hav e now pursued these observations in greater depth. An assay system was developed which separated the stimulation of macrophages by IFN gamma plus LPS, and the actual production of nitric oxide (NO). It was foun d that macrophages do not produce NO until they have been stimulated b y IFN gamma plus LPS for a period of 10 h. NO is produced during the s ubsequent 10 h, even though IFN gamma plus LPS are not longer present. DHA, if present, inhibited only during the initial 10 h stimulation; DHA did not inhibit the production of NO by macrophages which had prev iously been stimulated by IFN gamma plus LPS, and were already produci ng NO. It was also found that DHA was less inhibitory if given prior t o the IFN gamma plus LPS stimulation. In a dose-responsive manner, DHA inhibited the increased abundance of iNOS mRNA by macrophages stimula ted by IFN gamma plus LPS. NO contributes to the host defense against Listeria monocytogenes and other intracellular pathogens. We therefore investigated the ability of DHA to inhibit NO production by macrophag es stimulated by IFN gamma plus Listeria monocytogenes in vitro; DHA i nhibited transcription of the iNOS gene and also the listeriocidal act ivity of activated macrophages. Inhibition of NO production by DHA may contribute to the increased susceptibility of the fetoplacental unit and neonate to intracellular infections. (C) 1998 Elsevier Science Ire land Ltd. All rights reserved.