Docosahexaenoic acid, a major constituent of fetal serum and fish oil diets, inhibits IFNγ-induced Ia-expression by murine macrophages in vitro

Decreased la expression by macrophages may account for the increased susceptibility of fetuses and neonates to infection. We chose to investigate the role of docosahexaenoic acid (DHA), an omega-3 fatty acid, on Ia expression in vitro, because neonatal serum concentrations of DHA (100-150 μM) are approximately 50 times higher than in the adult. In addition, DHA is a major component of fish-oil diets that ameliorate some autoimmune diseases and prevent renal allograft rejection. DHA inhibited IFN-γ-induced Ia expression with a half-maximal inhibitory concentration of 25 μM. The inhibition was not caused by nonspecific damage, because oxidative metabolism via the mitochondrial electron-transport chain was not inhibited. There were strict biochemical requirements for inhibition of Ia expression. Polyenoic fatty acids with 22 carbons were more inhibitory than those with 20 carbons. Among 22-carbon fatty acids, those with more double bonds, and, in particular, with a double bond in the omega-3 position, were more inhibitory. Although DHA is known to inhibit cyclooxygenase and thus the production of eicosanoids, indomethacin did not inhibit la expression. This indicated that inhibition of cyclooxygenase was not responsible for inhibition of Ia expression. We divided induction of Ia expression by IFN-γ into four phases, with IFN-γ being present only during the second phase. DHA was most inhibitory when given before or with the IFN-γ. This indicated that DHA inhibited early steps in IFN-γ-induced Ia expression. Consistent with this idea, we found that DHA inhibited the increase in mRNA transcripts for Iaβ^b, as assayed by Northern blotting. In summary, we found that DHA, a major component of fetal and neonatal sera as well as fish-oil diets, inhibited IFN-γ-induced macrophage Ia expression in vitro by preventing increases in Ia mRNA transcripts.