二硫代氨基甲酸吡咯烷对细菌脂多糖引起的两种类型急性肝损伤的不同效应
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摘要
给予卡介苗(BCG)预处理的小鼠低剂量的细菌脂多糖(LPS)引起小鼠急性肝脏损伤,表现为肝脏大量巨噬细胞浸润,伴有高水平的肿瘤坏死因子α(TNF-α)的产生;氨基半乳糖(GalN)和LPS共处理可诱导TNF-α介导的、以肝脏细胞凋亡为主要特征的急性肝损伤。核因子κB(NF-κB)激活在两种TNF-α介导的急性肝损伤过程中均起重要作用,但发挥的效应可能不同。二硫代氨基甲酸吡咯烷(PDTC)是NF-κB活性抑制剂。本研究通过观察PDTC对LPS诱导小鼠两种急性肝损伤的不同效应,以阐明NF-κB激活在这两种肝损伤中的作用。
为探讨PDTC对给予BCG预处理的小鼠低剂量的LPS引起的急性肝损伤的效应,本实验设置对照组、LPS组、BCG组、BCG/LPS组、PDTC+BCG/LPS组和PDTC组。除对照组和LPS组外,各组小鼠经尾静脉注射BCG(2.5 mg/0.2 mL/只),10 d后,BCG/LPS组给予LPS(0.2 mg/kg,ip),PDTC+BCG/LPS组于LPS(0.2 mg/kg,ip)前24 h和2 h分别给予PDTC(100+100 mg/kg,ip),LPS组单纯给予LPS(0.2 mg/kg,ip),PDTC组单纯给予小鼠PDTC(100+100 mg/kg,ip),BCG组和对照组给予等体积生理盐水(saline)。每组15只小鼠被用于观察LPS处理后72 h内的动物死亡情况;每组6只小鼠于LPS处理后1.5 h被取血、处死和留取肝脏,用RT-PCR检测肝脏组织TNF-α、白细胞介素1β(IL-1β)和IL-6 mRNA表达水平,用EMSA分析肝脏NF-κB结合活性,用ELISA测定血清TNF-α含量;每组12只小鼠于LPS处理后6 h取血、处死和留取肝脏,测定血清丙氨酸转氨酶(ALT)活力、一氧化氮(NO)水平和肝组织还原型谷胱甘肽(GSH)含量,并对肝组织切片行常规HE染色。结果发现,给予BCG预处理的小鼠低剂量的LPS引起40%小鼠死亡,显著升高血清ALT活力并伴有肝脏坏死和大量的炎性细胞浸润;BCG/LPS处理激活肝脏NF-κB结合活性,上调肝脏TNF-α表达,降低肝脏GSH水平和升高NO生成;PDTC明显抑制肝脏NF-κB活性并下调肝脏TNF-α表达,升高肝脏GSH含量和降低NO生成;PDTC预处理显著降低BCG/LPS模型组血清ALT活力,减轻BCG/LPS引起的肝脏炎症和坏死并降低小鼠死亡率。
为研究PDTC对GalN/LPS诱导小鼠急性肝损伤的效应,本实验设置对照组、LPS组、GalN组、GalN/LPS组、PDTC+GalN/LPS组和PDTC组。GalN/LPS组同时给予小鼠LPS(20μg/kg,ip)和GalN(600 mg/kg,ip),PDTC+GalN/LPS组小鼠于LPS(20μg/kg,ip)和GalN(600 mg/kg,ip)共处理前24 h和2 h分别经腹腔注射PDTC(100+100 mg/kg),LPS组、GalN组和PDTC组分别单纯给予小鼠LPS(20μg/kg,ip)、GalN(600 mg/kg,ip)或PDTC(100+100 mg/kg),对照组给予等容积生理盐水。每组10只小鼠被用于观察LPS处理后72 h内的动物死亡情况;每组6只小鼠于LPS处理后1.5 h被取血、处死并留取肝脏,用RT-PCR检测肝脏组织TNF-α、IL-1β和IL-6 mRNA表达水平,用EMSA分析肝脏NF-κB活性,用ELISA法测定血清TNF-α含量;每组12只小鼠于LPS处理后6 h取血、处死并留取肝脏,测定血清ALT活力、NO水平和肝组织GSH含量,用比色法检测肝脏caspase-3活性,用TUNEL技术和DNA断裂分析方法检测肝脏细胞凋亡,并对肝组织切片行常规HE染色。结果显示,GalN/LPS共处理引起90%小鼠死亡,显著升高血清ALT活力和肝脏caspase-3活性,诱导肝脏细胞凋亡和炎性细胞浸润;GalN/LPS共处理引起肝脏GSH损耗和NO生成;PDTC预处理抑制GalN/LPS引起的肝脏TNF-α表达、升高肝脏GSH水平并降低NO生成,但PDTC反而加重GalN/LPS引起的肝脏细胞凋亡、进一步升高血清ALT活力、加重肝脏充血和坏死以及加速小鼠死亡。
上述研究结果提示,PDTC对LPS诱导的两种急性肝损伤有不同效应。一方面,PDTC预处理可能通过抑制肝脏Kupffer细胞NF-κB介导的TNF-α释放,保护BCG/LPS诱导的急性肝损伤;另一方面,PDTC预处理则可能通过抑制肝脏实质细胞NF-κB介导的抗凋亡机制,加重GalN/LPS诱导的急性肝损伤。
Mice primed with Bacillus Calmette-Guerin (BCG) were challenged with lipopolysaccharide (LPS) to induce acute liver injury, with macrophages infiltration and massive release of tumor necrosis factor alpha (TNF-α). Mice were co-injected with d-galactosamine (GalN) and LPS to induce TNF-α-mediated apoptotic liver injury. Nuclear factor kappa B (NF-κB) activation might play important roles on LPS-induced liver injury in two different models of fulminant hepatitis. Pyrrolidine dithiocarbamate (PDTC) is an inhibitor of NF-κB activation. The present study was to investigate the effects of PDTC on LPS-induced liver injury in two different models of fulminant hepatitis.
To explore the effects of PDTC on BCG/LPS-induced acute liver injury, mice were randomly divided into six groups. All mice except control groups were infected intravenously (i.v.) with BCG (2.5 mg, suspended in 0.2 mL saline). Ten days later, mice in BCG/LPS group were injected with LPS (0.2 mg/kg, i.p.). Mice in BCG/LPS+ PDTC group were injected with two doses of PDTC, one (100 mg/kg, i.p.) at 24 h before LPS and the other at 2 h before LPS (0.2 mg/kg, i.p.). Mice in control groups were intraperitoneally (i.p.) administrated with LPS (0.2 mg/kg), PDTC (100 mg/kg) or saline. Fifteen mice in each group were observed for animal survival within 72 h after LPS treatment. Six mice in each group were sacrificed 1.5 h after LPS administration for collecting blood serum and isolating livers. The expression of hepatic TNF-α, IL-1βand IL-6 mRNA were determined by RT-PCR. Hepatic NF-κB binding activity was measured using EMSA. Serum TNF-αlevel was analyzed by ELISA. Twelve mice in each group were sacrificed 6 h after LPS treatment. Blood serum was collected for measurement of alanine aminotransferase (ALT) and nitrate plus nitrite. Livers were dissected for glutathione (GSH) measurement and histological examination. Results showed that administration of LPS to mice primed with BCG resulted in 40% mortality, elevated serum ALT activity, induced hepatic necrosis and massive macrophages infiltration. BCG/LPS treatment triggered hepatic NF-κB binding activity, up-regulated expression of hepatic TNF-α, decreased hepatic GSH level, and increased serum NO production. PDTC pretreatment significantly inhibited hepatic NF-κB binding activity, down-regulated expression of hepatic TNF-α, attenuated BCG/LPS-induced hepatic GSH depletion and NO production. Correspondingly, PDTC pretreatment markedly reduced BCG/LPS-induced increase in serum ALT activity, attenuated hepatic inflammation and necrosis, and decreased mortality.
To investigate the effects of PDTC on GalN/LPS-induced acute liver injury, all mice were randomly divided into six groups. Mice in GalN/LPS group were co-injected with GalN (600 mg/kg, i.p.) and LPS (20μg/kg, i.p.). Mice in PDTC+GalN/LPS were injected with two doses of PDTC, one (100 mg/kg, i.p.) at 24 h before LPS and the other at 2 h before LPS (20μg/kg, i.p.). Mice in control groups were treated with LPS (20μg/kg, i.p.), GalN (600 mg/kg, i.p.), PDTC (100 mg/kg, i.p.) or saline. Ten mice in each group were observed for animal survival within 72 h after LPS treatment. Six mice in each group were sacrificed 1.5 h after LPS for collecting blood serum and isolating livers. The expression of hepatic TNF-α, IL-1βand IL-6 mRNA was determined by RT-PCR. Hepatic NF-κB binding activity was measured using EMSA. Serum TNF-αlevel was analyzed by ELISA. Twelve mice in each group were sacrificed 6 h after LPS treatment. Blood serum was collected for measurement of ALT and nitrate plus nitrite. Livers were dissected for measurements of GSH content, caspase-3 activity and hepatocellular apoptosis and histological examination. Results showed that co-injection of GalN and LPS led to 90% mortality, increased serum ALT activity and hepatic caspase-3 activity, triggered hepatocellular apoptosis and massive macrophages infiltration, decreased hepatic GSH level, and increased NO production. PDTC pretreatment significantly inhibited GalN/LPS-induced expression of hepatic TNF-αand attenuated hepatic GSH depletion and NO production. In contrast, PDTC aggravated GalN/LPS-triggered hepatocellular apoptosis, increased serum ALT activity, exacerbated hepatic hemorrhage and necrosis, and accelerated death.
Taken together, our results suggest that PDTC plays differential effects on LPS-induced liver injury in two different models of fulminant hepatitis. PDTC pretreatment protects mice against BCG/LPS-induced acute liver injury via inhibiting NF-κB activation and TNF-αrelease. Conversely, PDTC aggravates GalN/LPS-induced acute liver injury through repressing NF-κB-mediated anti-apoptotic effect in hepatocytes.
为探讨PDTC对给予BCG预处理的小鼠低剂量的LPS引起的急性肝损伤的效应,本实验设置对照组、LPS组、BCG组、BCG/LPS组、PDTC+BCG/LPS组和PDTC组。除对照组和LPS组外,各组小鼠经尾静脉注射BCG(2.5 mg/0.2 mL/只),10 d后,BCG/LPS组给予LPS(0.2 mg/kg,ip),PDTC+BCG/LPS组于LPS(0.2 mg/kg,ip)前24 h和2 h分别给予PDTC(100+100 mg/kg,ip),LPS组单纯给予LPS(0.2 mg/kg,ip),PDTC组单纯给予小鼠PDTC(100+100 mg/kg,ip),BCG组和对照组给予等体积生理盐水(saline)。每组15只小鼠被用于观察LPS处理后72 h内的动物死亡情况;每组6只小鼠于LPS处理后1.5 h被取血、处死和留取肝脏,用RT-PCR检测肝脏组织TNF-α、白细胞介素1β(IL-1β)和IL-6 mRNA表达水平,用EMSA分析肝脏NF-κB结合活性,用ELISA测定血清TNF-α含量;每组12只小鼠于LPS处理后6 h取血、处死和留取肝脏,测定血清丙氨酸转氨酶(ALT)活力、一氧化氮(NO)水平和肝组织还原型谷胱甘肽(GSH)含量,并对肝组织切片行常规HE染色。结果发现,给予BCG预处理的小鼠低剂量的LPS引起40%小鼠死亡,显著升高血清ALT活力并伴有肝脏坏死和大量的炎性细胞浸润;BCG/LPS处理激活肝脏NF-κB结合活性,上调肝脏TNF-α表达,降低肝脏GSH水平和升高NO生成;PDTC明显抑制肝脏NF-κB活性并下调肝脏TNF-α表达,升高肝脏GSH含量和降低NO生成;PDTC预处理显著降低BCG/LPS模型组血清ALT活力,减轻BCG/LPS引起的肝脏炎症和坏死并降低小鼠死亡率。
为研究PDTC对GalN/LPS诱导小鼠急性肝损伤的效应,本实验设置对照组、LPS组、GalN组、GalN/LPS组、PDTC+GalN/LPS组和PDTC组。GalN/LPS组同时给予小鼠LPS(20μg/kg,ip)和GalN(600 mg/kg,ip),PDTC+GalN/LPS组小鼠于LPS(20μg/kg,ip)和GalN(600 mg/kg,ip)共处理前24 h和2 h分别经腹腔注射PDTC(100+100 mg/kg),LPS组、GalN组和PDTC组分别单纯给予小鼠LPS(20μg/kg,ip)、GalN(600 mg/kg,ip)或PDTC(100+100 mg/kg),对照组给予等容积生理盐水。每组10只小鼠被用于观察LPS处理后72 h内的动物死亡情况;每组6只小鼠于LPS处理后1.5 h被取血、处死并留取肝脏,用RT-PCR检测肝脏组织TNF-α、IL-1β和IL-6 mRNA表达水平,用EMSA分析肝脏NF-κB活性,用ELISA法测定血清TNF-α含量;每组12只小鼠于LPS处理后6 h取血、处死并留取肝脏,测定血清ALT活力、NO水平和肝组织GSH含量,用比色法检测肝脏caspase-3活性,用TUNEL技术和DNA断裂分析方法检测肝脏细胞凋亡,并对肝组织切片行常规HE染色。结果显示,GalN/LPS共处理引起90%小鼠死亡,显著升高血清ALT活力和肝脏caspase-3活性,诱导肝脏细胞凋亡和炎性细胞浸润;GalN/LPS共处理引起肝脏GSH损耗和NO生成;PDTC预处理抑制GalN/LPS引起的肝脏TNF-α表达、升高肝脏GSH水平并降低NO生成,但PDTC反而加重GalN/LPS引起的肝脏细胞凋亡、进一步升高血清ALT活力、加重肝脏充血和坏死以及加速小鼠死亡。
上述研究结果提示,PDTC对LPS诱导的两种急性肝损伤有不同效应。一方面,PDTC预处理可能通过抑制肝脏Kupffer细胞NF-κB介导的TNF-α释放,保护BCG/LPS诱导的急性肝损伤;另一方面,PDTC预处理则可能通过抑制肝脏实质细胞NF-κB介导的抗凋亡机制,加重GalN/LPS诱导的急性肝损伤。
Mice primed with Bacillus Calmette-Guerin (BCG) were challenged with lipopolysaccharide (LPS) to induce acute liver injury, with macrophages infiltration and massive release of tumor necrosis factor alpha (TNF-α). Mice were co-injected with d-galactosamine (GalN) and LPS to induce TNF-α-mediated apoptotic liver injury. Nuclear factor kappa B (NF-κB) activation might play important roles on LPS-induced liver injury in two different models of fulminant hepatitis. Pyrrolidine dithiocarbamate (PDTC) is an inhibitor of NF-κB activation. The present study was to investigate the effects of PDTC on LPS-induced liver injury in two different models of fulminant hepatitis.
To explore the effects of PDTC on BCG/LPS-induced acute liver injury, mice were randomly divided into six groups. All mice except control groups were infected intravenously (i.v.) with BCG (2.5 mg, suspended in 0.2 mL saline). Ten days later, mice in BCG/LPS group were injected with LPS (0.2 mg/kg, i.p.). Mice in BCG/LPS+ PDTC group were injected with two doses of PDTC, one (100 mg/kg, i.p.) at 24 h before LPS and the other at 2 h before LPS (0.2 mg/kg, i.p.). Mice in control groups were intraperitoneally (i.p.) administrated with LPS (0.2 mg/kg), PDTC (100 mg/kg) or saline. Fifteen mice in each group were observed for animal survival within 72 h after LPS treatment. Six mice in each group were sacrificed 1.5 h after LPS administration for collecting blood serum and isolating livers. The expression of hepatic TNF-α, IL-1βand IL-6 mRNA were determined by RT-PCR. Hepatic NF-κB binding activity was measured using EMSA. Serum TNF-αlevel was analyzed by ELISA. Twelve mice in each group were sacrificed 6 h after LPS treatment. Blood serum was collected for measurement of alanine aminotransferase (ALT) and nitrate plus nitrite. Livers were dissected for glutathione (GSH) measurement and histological examination. Results showed that administration of LPS to mice primed with BCG resulted in 40% mortality, elevated serum ALT activity, induced hepatic necrosis and massive macrophages infiltration. BCG/LPS treatment triggered hepatic NF-κB binding activity, up-regulated expression of hepatic TNF-α, decreased hepatic GSH level, and increased serum NO production. PDTC pretreatment significantly inhibited hepatic NF-κB binding activity, down-regulated expression of hepatic TNF-α, attenuated BCG/LPS-induced hepatic GSH depletion and NO production. Correspondingly, PDTC pretreatment markedly reduced BCG/LPS-induced increase in serum ALT activity, attenuated hepatic inflammation and necrosis, and decreased mortality.
To investigate the effects of PDTC on GalN/LPS-induced acute liver injury, all mice were randomly divided into six groups. Mice in GalN/LPS group were co-injected with GalN (600 mg/kg, i.p.) and LPS (20μg/kg, i.p.). Mice in PDTC+GalN/LPS were injected with two doses of PDTC, one (100 mg/kg, i.p.) at 24 h before LPS and the other at 2 h before LPS (20μg/kg, i.p.). Mice in control groups were treated with LPS (20μg/kg, i.p.), GalN (600 mg/kg, i.p.), PDTC (100 mg/kg, i.p.) or saline. Ten mice in each group were observed for animal survival within 72 h after LPS treatment. Six mice in each group were sacrificed 1.5 h after LPS for collecting blood serum and isolating livers. The expression of hepatic TNF-α, IL-1βand IL-6 mRNA was determined by RT-PCR. Hepatic NF-κB binding activity was measured using EMSA. Serum TNF-αlevel was analyzed by ELISA. Twelve mice in each group were sacrificed 6 h after LPS treatment. Blood serum was collected for measurement of ALT and nitrate plus nitrite. Livers were dissected for measurements of GSH content, caspase-3 activity and hepatocellular apoptosis and histological examination. Results showed that co-injection of GalN and LPS led to 90% mortality, increased serum ALT activity and hepatic caspase-3 activity, triggered hepatocellular apoptosis and massive macrophages infiltration, decreased hepatic GSH level, and increased NO production. PDTC pretreatment significantly inhibited GalN/LPS-induced expression of hepatic TNF-αand attenuated hepatic GSH depletion and NO production. In contrast, PDTC aggravated GalN/LPS-triggered hepatocellular apoptosis, increased serum ALT activity, exacerbated hepatic hemorrhage and necrosis, and accelerated death.
Taken together, our results suggest that PDTC plays differential effects on LPS-induced liver injury in two different models of fulminant hepatitis. PDTC pretreatment protects mice against BCG/LPS-induced acute liver injury via inhibiting NF-κB activation and TNF-αrelease. Conversely, PDTC aggravates GalN/LPS-induced acute liver injury through repressing NF-κB-mediated anti-apoptotic effect in hepatocytes.
引文
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35. Hsieh YH, Su IJ, Wang HC, et al. Pre-S mutant surface antigens in chronic hepatitisB virus infection induce oxidative stress and DNA damage. Carcinogenesis, 2004; 25(10): 2023-2032.
36. Tsuji K, Kwon AH, Yoshida H, et al. Free radical scavenger (edaravone) prevents endotoxin-induced liver injury after partial hepatectomy in rats. J Hepatol, 2005; 42(1): 94-101.
37. Basu S. Carbon tetrachloride-induced lipid peroxidation: eicosanoid formation and their regulation by antioxidant nutrients. Toxicology, 2003; 189(1-2): 113-127.
38. Dey A, Cederbaum AI. Alcohol and oxidative liver injury. Hepatology, 2006; 43(2 suppl 1): S63-74.
39. Shi X, Leonard SS, Wang S, et al. Antioxidant properties of pyrrolidine dithiocarbamate and its protection against Cr (VI)-induced DNA strand breakage. Ann Clin Lab Sci, 2000; 30(2): 209-216.
40. Wang GS, Liu GT. Role of nitric oxide in immunological liver damage in mice. Biochem Pharmacol, 1995; 49(9): 1277-1281.
41. Guler R, Olleros ML, Vesin D, et al. Inhibition of inducible nitric oxide synthase protects against liver injury induced by mycobacterial infection and endotoxins. J Hepatol, 2004; 41(5): 773-781.
42. Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science, 1996, 274(5288): 782-784.
43. Van Antwerp DJ, Martin SJ, Kafri T, et al. Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science, 1996; 274(5288): 787-789.
44. Xu Y, Bialik S, Jones BE, et al. NF-kappaB inactivation converts a hepatocyte cell line TNF-alpha response from proliferation to apoptosis. Am J Physiol, 1998; 275(4 pt 1): C1058-1066.
45. Nagaki M, Naiki T, Brenner DA, et al. Tumor necrosis factor alpha prevents tumor necrosis factor receptor-mediated mouse hepatocyte apoptosis, but not fas-mediated apoptosis: role of nuclear factor-kappaB. Hepatology, 2000; 32(2): 1272-1279.
46. Liu S, Gallo DJ, Green AM, et al. Role of toll-like receptors in changes in gene expression and NF-kappa B activation in mouse hepatocytes stimulated with lipopolysaccharide. Infect Immun, 2002; 70(7): 3433-3442.
47. Tran-Thi TA, Decker K, Baeuerle A. Differential activation of transcription factors NF-kappa B and AP-1 in rat liver macrophages. Hepatology, 1995; 22(2): 613-619.
1. Pitti RM, Marsters SA, Lawrence DA, et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature, 1998; 396(6712): 699-703.
2. Bai C, Connolly B, Metzker ML, et al. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster. Proc Natl Acad Sci, 2000; 97(3): 1230-1235.
3. Yu KY, Kwon B, Ni J, et al. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem, 1999; 274(20): 13733-13736.
4. Wu Y, Guo E, Yu J, et al. High DcR3 expression predicts stage pN2-3 in gastric cancer. Am J Clin Oncol, 2008; 31(1): 79-83.
5. Arakawa Y, Tachibana O, Hasegawa M, et al. Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma. Acta Neuropathol, 2005; 109(3): 294-298.
6. Ohshima K, Haraoka S, Sugihara M, et al. Amplification and expression of a decoy receptor for fas ligand (DcR3) in virus (EBV or HTLV-I) associated lymphomas. Cancer Lett, 2000; 160(1): 89-97.
7. Shen HW, Gao SL, Wu YL, et al. Overexpression of decoy receptor 3 in hepatocellular carcinoma and its association with resistance to Fas ligand-mediated apoptosis. World J Gastroenterol, 2005; 11(38): 5926-5930.
8. Tsuji S, Hosotani R, Yonehara S, et al. Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma. Int J Cancer, 2003; 106(1): 17-25.
9. Otsuki T, Tomokuni A, Sakaguchi H, et al. Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients. Clin ExpImmunol, 2000, 119(2): 323-327.
10. Wan X, Shi G, Semenuk M, et al. DcR3/TR6 modulates immune cell interactions. J Cell Biochem, 2003; 89(3): 603-612.
11. Kim S, McAuliffe WJ, Zaritskaya LS, et al. Selective induction of tumor necrosis receptor factor 6/decoy receptor 3 release by bacterial antigens in human monocytes and myeloid dendritic cells. Infect Immun, 2004; 72(1): 89-93.
12. Kim S, Fotiadu A, Kotoula V. Increased expression of soluble decoy receptor 3 in acutely inflamed intestinal epithelia. Clin Immunol, 2005; 115(3): 286-294.
13. Gill RM, Hunt IS. Soluble receptor (DcR3) and cellular inhibitor of apoptosis-2 (cIAP-2) protect human cytotrophoblast cells against LIGHT-mediated apoptosis. Am J Pathol, 2004; 165(1): 309-317.
14. Wan X, Zhang J, Luo H , et al. TNR family costimulatory signals into human T cells. J Immunol, 2002; 169(12): 6813-6821.
15. Migone TS, Zhang J, Luo X, et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity, 2002; 16(3): 479-492.
16. Tan KB, Harrop J, Reddy M, et al. Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene, 1997; 204(1-2): 35-46.
17. Wu YY, Chang YC, Hsu TL, et al. Sensitization of cells to TRAIL-induced apoptosis by decoy receptor 3. Biol Chem, 2004; 279(42): 44211-44218.
18. Shi G, Wu Y, Zhang J. et al. Death decoy receptor TR6/DcR3 inhibits T cell chemotaxis in vitro and in vivo. J Immunol, 2003; 171(7): 3407-3414.
19. Hsu TL, Wu YY, Chang YC, et al. Attenuation of Th1 response in decoy receptor 3 transgenic mice. J Immunol, 2005; 175(8): 5135-5145.
20. Shi G, Luo H, Wan X, et al. Mouse T cells receive costimulatory signals from LIGHT, a TNF family member. Blood, 2002; 100(9): 3279-3286.
21. Hsu MJ, Lin WW, Tsao WC, et al. Enhanced adhesion of monocytes via reversesignaling triggered by decoy receptor 3. Exp Cell Res, 2004; 292(2): 241-251.
22. Yang CR, Hsieh SL, Teng CM, et al. Soluble decoy receptor 3 induces angiogenesis by neutralization of TL1A, a cytokine belonging to tumor necrosis factor superfamily and exhibiting angiostatic action. Cancer Res, 2004; 64(3): 1122-1129.
23. Wang CR, Wang JH, Hsieh SL, et al. Decoy receptor 3(DcR3) induces osteoclast formation from monocyte/macrophage lineagep recursor cells. Cell Death Differ, 2004; 11(supp 1): S97-107.
24. Yang CR, Hsieh SL, Ho FM, et al. Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappa B-dependent up-regulation of intercellular adhesion molecule-1, VCAM-1, and IL-8 expression. J Immunol, 2005; 174(3): 1647-1656.
25. Chang YC, Chan YH, Jackson DG, et al. The glycosaminoglycan-binding domain of decoy receptor 3 is essential for induction of monocyte adhesion. J Immunol, 2006; 176(1): 173-180.
26. Matute-Bello G, LilesWC, Frevert CW, et al. Blockade of the Fas/FasL system improves pneumococcal clearance from the lungs without preventing dissemination of bacteria to the spleen. J Infect Dis, 2005; 191(4): 596-606.
27. Tang CH, Hsu TL, Lin WW, et al. Attenuation of bone mass and increase of osteoclast formation in decoy receptor 3 transgenic mice. J Biol Chem, 2007; 282(4): 2346-2354.
28. Wroblewski VJ, McCloud C, Davis K, et al. Pharmacokinetics, metabolic stability, and subcutaneous bioavailability of a genetically engineered analog of DcR3, FLINT [DcR3 (R218Q)], in cynomolgus monkeys and mice. Drug Metab Dispos, 2003; 31(4): 502-507.
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35. Hsieh YH, Su IJ, Wang HC, et al. Pre-S mutant surface antigens in chronic hepatitisB virus infection induce oxidative stress and DNA damage. Carcinogenesis, 2004; 25(10): 2023-2032.
36. Tsuji K, Kwon AH, Yoshida H, et al. Free radical scavenger (edaravone) prevents endotoxin-induced liver injury after partial hepatectomy in rats. J Hepatol, 2005; 42(1): 94-101.
37. Basu S. Carbon tetrachloride-induced lipid peroxidation: eicosanoid formation and their regulation by antioxidant nutrients. Toxicology, 2003; 189(1-2): 113-127.
38. Dey A, Cederbaum AI. Alcohol and oxidative liver injury. Hepatology, 2006; 43(2 suppl 1): S63-74.
39. Shi X, Leonard SS, Wang S, et al. Antioxidant properties of pyrrolidine dithiocarbamate and its protection against Cr (VI)-induced DNA strand breakage. Ann Clin Lab Sci, 2000; 30(2): 209-216.
40. Wang GS, Liu GT. Role of nitric oxide in immunological liver damage in mice. Biochem Pharmacol, 1995; 49(9): 1277-1281.
41. Guler R, Olleros ML, Vesin D, et al. Inhibition of inducible nitric oxide synthase protects against liver injury induced by mycobacterial infection and endotoxins. J Hepatol, 2004; 41(5): 773-781.
42. Beg AA, Baltimore D. An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science, 1996, 274(5288): 782-784.
43. Van Antwerp DJ, Martin SJ, Kafri T, et al. Suppression of TNF-alpha-induced apoptosis by NF-kappaB. Science, 1996; 274(5288): 787-789.
44. Xu Y, Bialik S, Jones BE, et al. NF-kappaB inactivation converts a hepatocyte cell line TNF-alpha response from proliferation to apoptosis. Am J Physiol, 1998; 275(4 pt 1): C1058-1066.
45. Nagaki M, Naiki T, Brenner DA, et al. Tumor necrosis factor alpha prevents tumor necrosis factor receptor-mediated mouse hepatocyte apoptosis, but not fas-mediated apoptosis: role of nuclear factor-kappaB. Hepatology, 2000; 32(2): 1272-1279.
46. Liu S, Gallo DJ, Green AM, et al. Role of toll-like receptors in changes in gene expression and NF-kappa B activation in mouse hepatocytes stimulated with lipopolysaccharide. Infect Immun, 2002; 70(7): 3433-3442.
47. Tran-Thi TA, Decker K, Baeuerle A. Differential activation of transcription factors NF-kappa B and AP-1 in rat liver macrophages. Hepatology, 1995; 22(2): 613-619.
1. Pitti RM, Marsters SA, Lawrence DA, et al. Genomic amplification of a decoy receptor for Fas ligand in lung and colon cancer. Nature, 1998; 396(6712): 699-703.
2. Bai C, Connolly B, Metzker ML, et al. Overexpression of M68/DcR3 in human gastrointestinal tract tumors independent of gene amplification and its location in a four-gene cluster. Proc Natl Acad Sci, 2000; 97(3): 1230-1235.
3. Yu KY, Kwon B, Ni J, et al. A newly identified member of tumor necrosis factor receptor superfamily (TR6) suppresses LIGHT-mediated apoptosis. J Biol Chem, 1999; 274(20): 13733-13736.
4. Wu Y, Guo E, Yu J, et al. High DcR3 expression predicts stage pN2-3 in gastric cancer. Am J Clin Oncol, 2008; 31(1): 79-83.
5. Arakawa Y, Tachibana O, Hasegawa M, et al. Frequent gene amplification and overexpression of decoy receptor 3 in glioblastoma. Acta Neuropathol, 2005; 109(3): 294-298.
6. Ohshima K, Haraoka S, Sugihara M, et al. Amplification and expression of a decoy receptor for fas ligand (DcR3) in virus (EBV or HTLV-I) associated lymphomas. Cancer Lett, 2000; 160(1): 89-97.
7. Shen HW, Gao SL, Wu YL, et al. Overexpression of decoy receptor 3 in hepatocellular carcinoma and its association with resistance to Fas ligand-mediated apoptosis. World J Gastroenterol, 2005; 11(38): 5926-5930.
8. Tsuji S, Hosotani R, Yonehara S, et al. Endogenous decoy receptor 3 blocks the growth inhibition signals mediated by Fas ligand in human pancreatic adenocarcinoma. Int J Cancer, 2003; 106(1): 17-25.
9. Otsuki T, Tomokuni A, Sakaguchi H, et al. Over-expression of the decoy receptor 3 (DcR3) gene in peripheral blood mononuclear cells (PBMC) derived from silicosis patients. Clin ExpImmunol, 2000, 119(2): 323-327.
10. Wan X, Shi G, Semenuk M, et al. DcR3/TR6 modulates immune cell interactions. J Cell Biochem, 2003; 89(3): 603-612.
11. Kim S, McAuliffe WJ, Zaritskaya LS, et al. Selective induction of tumor necrosis receptor factor 6/decoy receptor 3 release by bacterial antigens in human monocytes and myeloid dendritic cells. Infect Immun, 2004; 72(1): 89-93.
12. Kim S, Fotiadu A, Kotoula V. Increased expression of soluble decoy receptor 3 in acutely inflamed intestinal epithelia. Clin Immunol, 2005; 115(3): 286-294.
13. Gill RM, Hunt IS. Soluble receptor (DcR3) and cellular inhibitor of apoptosis-2 (cIAP-2) protect human cytotrophoblast cells against LIGHT-mediated apoptosis. Am J Pathol, 2004; 165(1): 309-317.
14. Wan X, Zhang J, Luo H , et al. TNR family costimulatory signals into human T cells. J Immunol, 2002; 169(12): 6813-6821.
15. Migone TS, Zhang J, Luo X, et al. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity, 2002; 16(3): 479-492.
16. Tan KB, Harrop J, Reddy M, et al. Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene, 1997; 204(1-2): 35-46.
17. Wu YY, Chang YC, Hsu TL, et al. Sensitization of cells to TRAIL-induced apoptosis by decoy receptor 3. Biol Chem, 2004; 279(42): 44211-44218.
18. Shi G, Wu Y, Zhang J. et al. Death decoy receptor TR6/DcR3 inhibits T cell chemotaxis in vitro and in vivo. J Immunol, 2003; 171(7): 3407-3414.
19. Hsu TL, Wu YY, Chang YC, et al. Attenuation of Th1 response in decoy receptor 3 transgenic mice. J Immunol, 2005; 175(8): 5135-5145.
20. Shi G, Luo H, Wan X, et al. Mouse T cells receive costimulatory signals from LIGHT, a TNF family member. Blood, 2002; 100(9): 3279-3286.
21. Hsu MJ, Lin WW, Tsao WC, et al. Enhanced adhesion of monocytes via reversesignaling triggered by decoy receptor 3. Exp Cell Res, 2004; 292(2): 241-251.
22. Yang CR, Hsieh SL, Teng CM, et al. Soluble decoy receptor 3 induces angiogenesis by neutralization of TL1A, a cytokine belonging to tumor necrosis factor superfamily and exhibiting angiostatic action. Cancer Res, 2004; 64(3): 1122-1129.
23. Wang CR, Wang JH, Hsieh SL, et al. Decoy receptor 3(DcR3) induces osteoclast formation from monocyte/macrophage lineagep recursor cells. Cell Death Differ, 2004; 11(supp 1): S97-107.
24. Yang CR, Hsieh SL, Ho FM, et al. Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappa B-dependent up-regulation of intercellular adhesion molecule-1, VCAM-1, and IL-8 expression. J Immunol, 2005; 174(3): 1647-1656.
25. Chang YC, Chan YH, Jackson DG, et al. The glycosaminoglycan-binding domain of decoy receptor 3 is essential for induction of monocyte adhesion. J Immunol, 2006; 176(1): 173-180.
26. Matute-Bello G, LilesWC, Frevert CW, et al. Blockade of the Fas/FasL system improves pneumococcal clearance from the lungs without preventing dissemination of bacteria to the spleen. J Infect Dis, 2005; 191(4): 596-606.
27. Tang CH, Hsu TL, Lin WW, et al. Attenuation of bone mass and increase of osteoclast formation in decoy receptor 3 transgenic mice. J Biol Chem, 2007; 282(4): 2346-2354.
28. Wroblewski VJ, McCloud C, Davis K, et al. Pharmacokinetics, metabolic stability, and subcutaneous bioavailability of a genetically engineered analog of DcR3, FLINT [DcR3 (R218Q)], in cynomolgus monkeys and mice. Drug Metab Dispos, 2003; 31(4): 502-507.