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Articles

Retinoic Acid and Lipopolysaccharide Act Synergistically to Increase Prostanoid Concentrations in Rats In Vivo¹

Yvan Devaux^*,2, Carole Seguin^*,2, Sandrine Grosjean^*,, Nicole de Talancé^**, Maryline Schwartz^**, Arlette Burlet, Faiez Zannad^*, Claude Meistelman, Paul-Michel Mertes^*, and Dan Ungureanu-Longrois^*,,3

^* Unité Propre d’Enseignement Supérieur Associée 971068, Faculté de Médecine, 54505 Vandoeuvre; Département d’Anesthésie-Réanimation Chirurgicale, ^** Laboratoire de Biologie Cellulaire, Centre Hospitalier Universitaire de Nancy, 54511 Vandoeuvre; Institut National de la Santé et de la Recherche Médicale Unité X 308, 54000 Nancy; and Laboratoire de Physiologie, Hôpital Maison Blanche, 51092 Reims, France

³To whom correspondence should be addressed. E-mail: d.longrois{at}chu-nancy.fr.

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.

KEY WORDS: • retinoids • prostaglandins • prostaglandin E synthase • nitric oxide • rats

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				C. Seguin-Devaux, Y. Devaux, V. Latger-Cannard, S. Grosjean, C. Rochette-Egly, F. Zannad, C. Meistelman, P.-M. Mertes, and D. Longrois Enhancement of the inducible NO synthase activation by retinoic acid is mimicked by RARalpha agonist in vivo Am J Physiol Endocrinol Metab, September 1, 2002; 283(3): E525 - E535. [Abstract] [Full Text] [PDF]