Nanji Amin A, Jokelainen Kalle, Tipoe George L, Rahemtulla Amir, Thomas Peter, Dannenberg Andrew J
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-4283, USA.
Am J Physiol Gastrointest Liver Physiol. 2003 Feb;284(2):G321-7. doi: 10.1152/ajpgi.00230.2002. Epub 2002 Aug 28.
Induction of NF-kappaB-mediated gene expression has been implicated in the pathogenesis of alcoholic liver disease (ALD). Curcumin, a phenolic antioxidant, inhibits the activation of NF-kappaB. We determined whether treatment with curcumin would prevent experimental ALD and elucidated the underlying mechanism. Four groups of rats (6 rats/group) were treated by intragastric infusion for 4 wk. One group received fish oil plus ethanol (FE); a second group received fish oil plus dextrose (FD). The third and fourth groups received FE or FD supplemented with 75 mg. kg(-1). day(-1) of curcumin. Liver samples were analyzed for histopathology, lipid peroxidation, NF-kappaB binding, TNF-alpha, IL-12, monocyte chemotactic protein-1, macrophage inflammatory protein-2, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nitrotyrosine. Rats fed FE developed fatty liver, necrosis, and inflammation, which was accompanied by activation of NF-kappaB and the induction of cytokines, chemokines, COX-2, iNOS, and nitrotyrosine formation. Treatment with curcumin prevented both the pathological and biochemical changes induced by alcohol. Because endotoxin and the Kupffer cell are implicated in the pathogenesis of ALD, we investigated whether curcumin suppressed the stimulatory effects of endotoxin in isolated Kupffer cells. Curcumin blocked endotoxin-mediated activation of NF-kappaB and suppressed the expression of cytokines, chemokines, COX-2, and iNOS in Kupffer cells. Thus curcumin prevents experimental ALD, in part by suppressing induction of NF-kappaB-dependent genes.
核因子-κB(NF-κB)介导的基因表达的诱导与酒精性肝病(ALD)的发病机制有关。姜黄素是一种酚类抗氧化剂,可抑制NF-κB的激活。我们确定姜黄素治疗是否能预防实验性ALD,并阐明其潜在机制。将四组大鼠(每组6只大鼠)通过胃内灌注给药4周。一组给予鱼油加乙醇(FE);第二组给予鱼油加葡萄糖(FD)。第三组和第四组给予补充有75 mg·kg-1·天-1姜黄素的FE或FD。对肝脏样本进行组织病理学、脂质过氧化、NF-κB结合、肿瘤坏死因子-α(TNF-α)、白细胞介素-12(IL-12)、单核细胞趋化蛋白-1、巨噬细胞炎性蛋白-2、环氧合酶-2(COX-2)、诱导型一氧化氮合酶(iNOS)和硝基酪氨酸分析。喂食FE的大鼠出现脂肪肝、坏死和炎症,同时伴有NF-κB的激活以及细胞因子、趋化因子、COX-2、iNOS的诱导和硝基酪氨酸的形成。姜黄素治疗可预防酒精诱导的病理和生化变化。由于内毒素和库普弗细胞与ALD的发病机制有关,我们研究了姜黄素是否能抑制内毒素对分离的库普弗细胞的刺激作用。姜黄素可阻断内毒素介导的NF-κB激活,并抑制库普弗细胞中细胞因子、趋化因子、COX-2和iNOS的表达。因此,姜黄素可预防实验性ALD,部分原因是通过抑制NF-κB依赖性基因的诱导。