Retinoic acid and lipopolysaccharide act synergistically to increase prostanoid concentrations in rats in vivo

Vitamin A and its active metabolite retinoic acid (RA) modulate host-pathogen interactions by interfering with the host immune and inflammatory response including prostaglandin (PG) biosynthesis. The effects of RA on phospholipase A₂ (PLA₂) and cyclooxygenase (COX) isoforms in vitro are controversial, and few in vivo studies exist. We investigated the in vivo effects of RA on PG biosynthesis in the presence or absence of lipopolysaccharide (LPS) in rats. RA alone [10 mg/(kg·d) for 5 d] increased plasma and liver PG concentrations by increasing COX-1 protein expression (twofold that of control rats). RA acted synergistically with LPS to increase plasma (400-fold) and liver (15-fold) concentrations of prostaglandin E₂ (PGE₂) and significantly, but to a lesser extent, other PG compared with RA rats, in the absence of major differences in PLA₂ expression or activity or COX-1 and COX-2 mRNA or protein expression. The RA+LPS-mediated increase in PGE₂ was significantly attenuated (97%) by aminoguanidine (AG), a relatively specific inhibitor of the inducible nitric oxide synthase (NOS2), consistent with the previously reported synergistic effect of RA and LPS on NOS2 expression and activity. In addition, RA and LPS induced the expression of the microsomal isoform of PGE synthase (mPGES). In conclusion, in vivo, RA and LPS increased PG and especially PGE₂ concentrations. The PGE₂ increase was associated with NOS2-mediated activation of COX and induction of mPGES. These results contribute to the characterization of the effects of vitamin A on the host inflammatory response.