Novitskiy Gennadiy, Ravi Rajani, Potter James J, Rennie-Tankersley Lynda, Wang Lan, Mezey Esteban
Department of Medicine, 921 Ross Research Building, The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205-2195, USA.
Alcohol Alcohol. 2005 Mar-Apr;40(2):96-101. doi: 10.1093/alcalc/agh116. Epub 2004 Nov 18.
Increased plasma tumour necrosis alpha (TNFalpha) and elevated monocyte nuclear factor kappa B (NF-kappaB) are associated with liver injury and inflammation in models of alcoholic liver disease and are found to be elevated in monocytes of patients with alcoholic hepatitis. Acetaldehyde enhances, whereas TNFalpha inhibits, transcription of the type I collagen promoters and type I collagen production. NF-kappaB, an inhibitor of the type I collagen promoters, is increased by both acetaldehyde and TNFalpha. This study determined the effects of acetaldehyde in comparison to the effects of TNFalpha on inhibitory kappa B-alpha (IkappaB-alpha) protein and NF-kappaB activation in hepatic stellate cells.
Activated rat hepatic stellate cells in culture were exposed to acetaldehyde or TNFalpha for short periods of time, following which the cells were harvested for the determination of IkappaB-alpha protein, IkappaB-alpha kinase activity and nuclear NF-kappaB.
Acetaldehyde increased IkappaB-alpha kinase activity and decreased IkappaB-alpha after 10 min of exposure, with recovery towards control levels at 20 min. In contrast, TNFalpha resulted in higher IkappaB-alpha kinase activity at 20 min than at 10 min, and similar low IkappaB-alpha at 10 and 20 min. Both acetaldehyde and TNFalpha enhanced nuclear NF-kappaB (p65), but acetaldehyde alone also increased NF-kappaB (p50).
TNFalpha and acetaldehyde independently activate NF-kappaB by rapid enhancement of IkappaB-alpha kinase activity and degradation of IkB-alpha protein. Increased TNFalpha is the principal mechanism for the elevation of NF-kappaB in severe alcoholic hepatitis. The elevation of NF-kappaB due to TNFalpha enhance liver injury, but inhibit fibrogenesis. In contrast, the effect of acetaldehyde in activating NF-kappaB is associated with increases in both liver injury and fibrogenesis, indicating that the effects of acetaldehyde on fibrogenesis are mediated by cytokines and by trans-acting factors other than NF-kappaB.
在酒精性肝病模型中，血浆肿瘤坏死因子α（TNFα）升高和单核细胞核因子κB（NF-κB）升高与肝损伤和炎症相关，且在酒精性肝炎患者的单核细胞中也发现其升高。乙醛可增强I型胶原启动子的转录和I型胶原的产生，而TNFα则抑制其转录。NF-κB是I型胶原启动子的抑制剂，乙醛和TNFα均可使其增加。本研究比较了乙醛和TNFα对肝星状细胞中抑制性κB-α（IkappaB-α）蛋白和NF-κB激活的影响。
将培养的活化大鼠肝星状细胞短时间暴露于乙醛或TNFα，之后收获细胞以测定IkappaB-α蛋白、IkappaB-α激酶活性和核NF-κB。
乙醛暴露10分钟后可增加IkappaB-α激酶活性并降低IkappaB-α，20分钟时恢复至对照水平。相比之下，TNFα在20分钟时的IkappaB-α激酶活性高于10分钟时，且在10分钟和20分钟时的IkappaB-α水平相似。乙醛和TNFα均可增强核NF-κB（p65），但仅乙醛也可增加NF-κB（p50）。
TNFα和乙醛通过快速增强IkappaB-α激酶活性和降解IkB-α蛋白来独立激活NF-κB。TNFα升高是重度酒精性肝炎中NF-κB升高的主要机制。TNFα导致的NF-κB升高会加重肝损伤，但抑制纤维化形成。相比之下，乙醛激活NF-κB的作用与肝损伤和纤维化形成的增加均相关，这表明乙醛对纤维化形成的影响是由细胞因子和NF-κB以外的反式作用因子介导的。
