Retinoic Acid and Lipopolysaccharide Act Synergistically to Increase Prostanoid Concentrations in Rats In Vivo

Abstract

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 A(2) (PLA(2)) 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 E(2) (PGE(2)) and significantly, 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 + LPS-mediated increase in PGE(2) 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 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 vitamin A on the host inflammatory response.

The oral administration of retinoic acid enhances nociceptive withdrawal reflexes in rats with soft-tissue inflammation

“…A single dose per day was chosen, instead of multiple doses, since it has been shown that a much better tolerance of retinoic acid is observed when using single doses [31]. Furthermore, the doses used in the present study have been shown to have anti-inflammatory properties in experimental models of nephropathy [21], and also to induce an increment in the prostaglandin E2 concentration in rats [4]. They were also well below the doses described as toxic in similar species [31].…”

“…The regulation of the synthesis of prostaglandins by ATRA is also controversial in in vitro preparations. However, using a similar protocol of administration of ATRA in rats, it has been shown that retinoic acid increases plasma and liver prostaglandin concentrations, especially prostaglandin E2, by increasing COX-1 protein expression and this enhancement is much greater in the presence of lipopolysaccharide [4]. It is well documented that COX enzymes and prostaglandins are involved in the central processing of nociceptive information (see for example [34], and references within), and especially in situations of inflammation.…”

“…Some studies, for example, have shown a clear relationship between retinoic acid and the generation of nitric oxide (NO) [9,12,28], prostaglandins [4,11] and the expression of cyclooxigenase 1 (COX-1) [23] and COX-2 [14,17]. All these mediators are involved in the generation or maintenance of sensitization and pain due to inflammation and are the targets for many painkillers studied in our lab among many others [7,10,26].…”

Prostaglandin E2 induces contraction of liver myofibroblasts by activating EP3 and FP prostanoid receptors

“…Previous reports show that liver injury or inflammation increases the local PGE 2 concentration in sinusoids up to several hundred or thousand nanomolar (Neuschafer‐Rube et al. , 1993; Devaux et al. , 2001).…”

Retinoids activate the irritant receptor TRPV1 and produce sensory hypersensitivity

“…For instance, ATRA treatment enhances TRPV1 protein expression and function in TRPV1-expressing SHSY5Y neuroblastoma cells (66). Retinoid signaling can also influence levels of other proinflammatory mediators, such as NGF and prostaglandins, which could change pain sensation under disease conditions such as diabetes mellitus (62,67).…”