TY - JOUR
T1 - Retinoic acid and host-pathogen interactions
T2 - Effects on inducible nitric oxide synthase in vivo
AU - Devaux, Yvan
AU - Grosjean, Sandrine
AU - Seguin, Carole
AU - David, Chantal
AU - Dousset, Brigitte
AU - Zannad, Faiez
AU - Meistelman, Claude
AU - De Talancé, Nicole
AU - Mertes, Paul Michel
AU - Ungureanu-Longrois, Dan
PY - 2000
Y1 - 2000
N2 - 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)-γ and IFN regulatory factor-1 mRNAs in several organs and increased IFN-γ 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.
AB - 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)-γ and IFN regulatory factor-1 mRNAs in several organs and increased IFN-γ 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.
KW - Interferon regulatory factor-1
KW - Interferon type II
KW - Lipopolysaccharide
KW - Nitric oxide
KW - Retinoids
UR - http://www.scopus.com/inward/record.url?scp=0033668022&partnerID=8YFLogxK
U2 - 10.1152/ajpendo.2000.279.5.e1045
DO - 10.1152/ajpendo.2000.279.5.e1045
M3 - Article
C2 - 11052959
AN - SCOPUS:0033668022
SN - 0193-1849
VL - 279
SP - E1045-E1053
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 5 42-5
ER -