Retinoic acid and host-pathogen interactions:: effects on inducible nitric oxide synthase in vivo
Retinoic acid and host-pathogen interactions:: effects on inducible nitric oxide synthase in vivo
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DOI：
10.1152/ajpendo.2000.279.5.e1045
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发表时间：
2000-11-01
影响因子：
5.1
通讯作者：
Ungureanu-Longrois, D
中科院分区：
文献类型：
--
作者：
Devaux, Y;Grosjean, S;Ungureanu-Longrois, D
维生素A及其代谢物维甲酸调节宿主对病原体的反应的机制尚不清楚。体外研究表明，维甲酸可降低内毒素或细胞因子刺激的几种细胞中诱导型一氧化氮合酶(NOS2，或iNOS)的表达，而iNOS是天然免疫的一个组成部分。本研究观察了维甲酸对内毒素刺激的NOS2表达的影响。大鼠每日给予全反式维甲酸(RA，10 mg/kg)或赋形剂，连续5d，随后给予脂多糖(4 mg/kg)或生理盐水，6h后处死。通过转录-聚合酶链式反应(RT-PCR)和蛋白印迹(Western-Blot)的表达以及血浆硝酸盐/亚硝酸盐积累来评估NOS2的活性。与以往的体外研究报道形成鲜明对比的是，RA显著增加了注射内毒素大鼠NOS2的mRNA、蛋白表达和血浆硝酸盐/亚硝酸盐浓度，但对注射生理盐水的大鼠无明显影响。这与白介素2、干扰素-γ和干扰素调节因子-1mRNAs在几个器官中的表达增加以及干扰素-γ的血浆浓度增加有关。RA显著增加内毒素注射大鼠的死亡率。一氧化氮合酶抑制剂氨基胍(内毒素注射前50 mg/kg)可显著减轻RA引起的死亡率增加。这些结果首次证明，体内补充维甲酸可增强脂多糖触发的NOS2通路的激活。
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)-gamma and IFN regulatory factor-1 mRNAs in several organs and increased IFN-gamma 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.