T. Khaireldin et al., TRANSCRIPTION OF THE MURINE INOS GENE IS INHIBITED BY DOCOSAHEXAENOICACID, A MAJOR CONSTITUENT OF FETAL AND NEONATAL SERA AS WELL AS FISH OILS, The Journal of experimental medicine, 183(3), 1996, pp. 1241-1246
Macrophage activation is deficient in the fetus and neonate when the s
erum concentrations of docosahexaenoic acid (DHA) are 150 mu M, or 10-
50-fold higher than in the adult. We now show that DHA inhibits produc
tion of nitric oxide (NO) by macrophages stimulated in vitro by IFN ga
mma plus LPS, or by IFN gamma plus TNF alpha. The half-maximal inhibit
ory activity of DHA was similar to 25 mu M. There were strict biochemi
cal requirements of the fatty acid for inhibition. Polyenoic fatty aci
ds with 22 carbons were more inhibitory than those with 20 carbons. Am
ong 22 carbon fatty acids, those with a greater number of double bonds
and a double bond in the n-3 position were more inhibitory. DHA was t
he most inhibitory of the polyenoic acids we tested. Inducible nitric
oxide synthase (iNOS) is the enzyme responsible for the production of
NO by macrophages. NO production is initiated after new iNOS enzyme is
synthesized following transcription of the iNOS gene. In macrophages
stimulated by IFN gamma plus LPS, DHA inhibited accumulation of iNOS m
RNA, as measured by Northern blotting, and iNOS transcription, as meas
ured by nuclear run-on assays. We transfected RAW 264.7 macrophages wi
th a construct containing the iNOS promoter fused to the chloramphenic
ol acetyl transferase gene. DHA inhibited activation of this promoter
by IFN gamma plus LPS. By inhibiting iNOS transcription in the fetus a
nd neonate, DHA may contribute to their increased susceptibility to in
fection.