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-pathog en interactions by interfering with the host immune and inflammatory respon se including prostaglandin (PG) biosynthesis. The effects of RA on phosphol ipase A(2) (PLA(2)) and cyclooxygenase (COX) isoforms in vitro are controve rsial, and few in vivo studies exist. We investigated the in vivo effects o f RA on PG biosynthesis in the presence or absence of lipopolysaccharicle ( LIPS) 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-fo ld) and liver (15-fold) concentrations of prostaglandin E-2 (PGE(2)) and si gnificantly, but to a lesser extent, other PG compared with RA rats, in the absence of major differences in PLA(2) expression or activity or COX-1 and COX-2 mRNA or protein expression. The RA + LIPS-mediated increase in PGE(2 ) was significantly attenuated (97%) by aminoguanidine (AG), a relatively s pecific inhibitor of the inducible nitric oxide synthase (NOS2), consistent with the previously reported synergistic effect of RA and LIPS on NOS2 exp ression 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 PGE(2) concentrations. The PGE(2) increase was associated with NOS2-mediated activation of COX and induction of mPGES . These results contribute to the characterization of the effects of vitami n A on the host inflammatory response.