Yu Jun, Hui Alex Y, Chu Eagle S H, Cheng Alfred S L, Go Minnie Y Y, Chan Henry L Y, Leung Wai K, Cheung Kin F, Ching Arthur K K, Chui Yiu L, Chan Ka K, Sung Joseph J Y
Department of Medicine and Therapeutics, Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, NT, Hong Kong.
Gut. 2007 Jul;56(7):991-9. doi: 10.1136/gut.2006.097923. Epub 2006 Dec 5.
It has been proved that cyclo-oxygenase-2 (COX-2) is rapidly induced by inflammatory mediators. However, it is not known whether overexpression of COX-2 in the liver is sufficient to promote activation or secretion of inflammatory factors leading to hepatitis.
To investigate the role forced expression of COX-2 in liver by using inducible COX-2 transgenic (TG) mice.
TG mice that overexpress the human COX-2 gene in the liver using the liver-specific transthyretin promoter and non-TG littermates were derived and fed the normal diet for up to 12 months. Hepatic prostaglandin E(2) (PGE(2)) content was determined using enzyme immunoassay, nuclear factor kappaB (NF-kappaB) activation by electrophoretic mobility shift assays, apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end labelling and proliferation by Ki-67 immunohistochemistry.
COX-2 TG mice exhibited strongly increased COX-2 and PGE(2), elevated serum alanine aminotransferase level and histological hepatitis. Hepatic COX-2 expression in the TG mice resulted in activation of NF-kappaB and inflammatory cytokine cascade, with a marked expression of the proinflammatory cytokines tumour necrosis factor (TNF)-alpha (9.4-fold), interleukin (IL)-6 (4.4-fold), IL-1beta (3.6-fold), and of the anti-inflammatory cytokine IL-10 (4.4-fold) and chemokine macrophage inflammatory protein-2 (3.2-fold). The inflammatory response of the COX-2 TG mice was associated with infiltration macrophages and lymphocytes, increased cell proliferation and high rates of cell apoptosis. Administration of the COX-2 inhibitor celecoxib in TG mice restored liver histology to normal.
Enhanced COX-2 expression in hepatocytes is sufficient to induce hepatitis by activating NF-kappaB, stimulating the secretion of proinflammatory cytokines, recruiting macrophage and altering cell kinetics. Inhibition of COX-2 represents a mechanism-based chemopreventive approach to hepatitis.
已证实环氧化酶-2（COX-2）可被炎症介质迅速诱导。然而，肝脏中COX-2的过表达是否足以促进炎症因子的激活或分泌从而导致肝炎尚不清楚。
通过使用可诱导型COX-2转基因（TG）小鼠研究肝脏中COX-2强制表达的作用。
构建利用肝脏特异性甲状腺素运载蛋白启动子在肝脏中过表达人COX-2基因的TG小鼠及其同窝非TG小鼠，并给予正常饮食长达12个月。采用酶免疫测定法测定肝脏前列腺素E2（PGE2）含量，通过电泳迁移率变动分析检测核因子κB（NF-κB）激活情况，利用末端脱氧核苷酸转移酶介导的dUTP-地高辛标记法检测细胞凋亡，通过Ki-67免疫组织化学检测细胞增殖情况。
COX-2 TG小鼠表现出COX-2和PGE2显著增加、血清丙氨酸氨基转移酶水平升高及组织学肝炎。TG小鼠肝脏中COX-2的表达导致NF-κB激活和炎症细胞因子级联反应，促炎细胞因子肿瘤坏死因子（TNF）-α（9.4倍）、白细胞介素（IL）-6（4.4倍）、IL-1β（3.6倍）以及抗炎细胞因子IL-10（4.4倍）和趋化因子巨噬细胞炎性蛋白-2（3.2倍）均有明显表达。COX-2 TG小鼠的炎症反应与巨噬细胞和淋巴细胞浸润、细胞增殖增加及高细胞凋亡率相关。给TG小鼠施用COX-2抑制剂塞来昔布可使肝脏组织学恢复正常。
肝细胞中COX-2表达增强足以通过激活NF-κB、刺激促炎细胞因子分泌、募集巨噬细胞和改变细胞动力学来诱导肝炎。抑制COX-2代表一种基于机制的肝炎化学预防方法。
