DOCOSAHEXAENOIC ACID, A MAJOR CONSTITUENT OF FETAL SERUM AND FISH-OILDIETS, INHIBITS IFN-GAMMA-INDUCED IA-EXPRESSION BY MURINE MACROPHAGESIN-VITRO

Decreased la expression by macrophages may account for the increased s usceptibility of fetuses and neonates to infection. We chose to invest igate the role of docosahexaenoic acid (DHA), an omega-3 fatty acid, o n la expression in vitro, because neonatal serum concentrations of DHA (100-150 mu M) are approximately 50 times higher than in the adult. I n addition, DHA is a major component of fish-oil diets that ameliorate some autoimmune diseases and prevent renal allograft rejection. DHA i nhibited IFN-gamma-induced la expression with a half-maximal inhibitor y concentration of 25 mu M. The inhibition was not caused by nonspecif ic damage, because oxidative metabolism via the mitochondrial electron -transport chain was not inhibited. There were strict biochemical requ irements for inhibition of la expression. Polyenoic fatty acids with 2 2 carbons were more inhibitory than those with 20 carbons. Among 22-ca rbon fatty acids, those with more double bonds, and, in particular, wi th a double bond in the omega-3 position, were more inhibitory. Althou gh DHA is known to inhibit cyclooxygenase and thus the production of e icosanoids, indomethacin did not inhibit la expression. This indicated that inhibition of cyclooxygenase was not responsible for inhibition of la expression. We divided induction of la expression by IFN-gamma i nto four phases, with IFN-gamma being present only during the second p hase. DHA was most inhibitory when given before or with the IFN-gamma. This indicated that DHA inhibited early steps in IFN-gamma-induced la expression. Consistent with this idea, we found that DHA inhibited th e increase in mRNA transcripts for la beta(b), as assayed by Northern blotting. In summary, we found that DHA, a major component of fetal an d neonatal sera as well as fish-oil diets, inhibited IFN-gamma-induced macrophage la expression in vitro by preventing increases in la mRNA transcripts.