Retinoic acid and host-pathogen interactions: effects on inducible nitric oxide synthase in vivo

• Published in: American journal of physiology: endocrinology and metabolism 2000-11, Vol.279 (5), p.E1045-E1053
• Main Authors: Devaux, Yvan, Grosjean, Sandrine, Seguin, Carole, David, Chantal, Dousset, Brigitte, Zannad, Faiez, Meistelman, Claude, De Talance, Nicole, Mertes, Paul-Michel, Ungureanu-Longrois, Dan
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; DNA-Binding Proteins - genetics; Gene Expression; Interferon Regulatory Factor-1; Interferon-gamma - genetics; Interleukin-1 - genetics; Interleukin-2 - genetics; Lipopolysaccharides - pharmacology; Male; Nitrates - blood; Nitric Oxide Synthase - analysis; Nitric Oxide Synthase - genetics; Nitric Oxide Synthase - metabolism; Nitric Oxide Synthase Type II; Nitrites - blood; Phosphoproteins - genetics; Rats; Rats, Inbred WKY; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Salmonella typhimurium; Tretinoin - pharmacology; Tumor Necrosis Factor-alpha - genetics
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.2000.279.5.E1045

1  Laboratory of Experimental Medicine and Surgery, Faculté de Médecine, 54505 Vandoeuvre; 2  Department of Anesthesia and Intensive Care, 3  Laboratory of Cellular Biology, Centre Hospitalier Universitaire de Nancy, 54511 Vandoeuvre; and 4  Laboratory of Biochemistry, Centre Hospitalier Universitaire de Nancy, Hôpital Central, 54035 Nancy, France Vitamin A and its metabolite retinoic acid modulate the host response to pathogens through poorly characterized mechanisms. In vitro studies have suggested that retinoic acid decreases inducible NO synthase (NOS2, or iNOS) expression, a component of innate immunity, in several cell types stimulated with lipopolysaccharide (LPS) or cytokines. This study investigated the effect of retinoic acid on LPS-stimulated NOS2 expression in vivo. Wistar-Kyoto rats received all- trans retinoic acid (RA, 10 mg/kg) or vehicle intraperitoneally daily for 5 days followed by LPS (4 mg/kg) or saline intraperitoneally and were killed 6 h later. NOS2 activation was estimated by mRNA (RT-PCR) and protein (Western-blot) expression and plasma nitrate/nitrite accumulation. In sharp contrast to previous in vitro study reports, RA significantly enhanced NOS2 mRNA, protein expression, and plasma nitrate/nitrite concentration in LPS-injected rats but not in saline-injected rats. This was associated with increased expression of interleukin-2, interferon (IFN)- and IFN regulatory factor-1 mRNAs in several organs and increased IFN- plasma concentration. RA significantly increased mortality in LPS-injected rats. The NOS inhibitor aminoguanidine (50 mg/kg before LPS injection) significantly attenuated the RA-mediated increase in mortality. These results demonstrate for the first time that RA supplementation in vivo enhances activation of the LPS-triggered NOS2 pathway. nitric oxide; retinoids; lipopolysaccharide; interferon type II; interferon regulatory factor-1