Activation of nuclear factor-κB during orthotopic liver transplantation in rats is protective and does not require Kupffer cells
Activation of nuclear factor-κB during orthotopic liver transplantation in rats is protective and does not require Kupffer cells
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DOI：
10.1002/lt.500050401
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发表时间：
1999-07-01
期刊：
影响因子：
--
通讯作者：
Brenner, DA
中科院分区：
文献类型：
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作者：
Bradham, CA;Schemmer, P;Brenner, DA
肝移植后再灌注导致肿瘤坏死因子- α (TNF - α)的诱导以及应激相关信号蛋白、c-Jun n-末端激酶（JNK）、活化蛋白-1 （AP-1）和核因子- κ B （nf - κ B）的激活。为了验证大鼠肝移植过程中Kupffer细胞参与信号转导级联激活的假设，使用氯化钆（GdCl3）从供肝中去除Kupffer细胞。然后评估移植后JNK、AP-1和nf - κ B的激活情况。结果表明，GdCl3处理无显著性差异。抑制这些应激信号的激活，尽管移植的肝脏已经耗尽了库普弗细胞并受到部分保护；再灌注损伤。移植诱导白细胞介素-6 （IL-6）和IL-10信使rna (mrna)， Kupffer细胞耗尽抑制其诱导。肝移植过程中TNF α mRNA和血清蛋白的诱导不受GdCl3的影响。这些结果表明，库普弗细胞不是肝移植后TNF α产生的主要来源，应激信号蛋白的激活独立于库普弗细胞发生。移植强烈激活转录因子NF-kappa B，其在体外阻断TNF α介导的肝细胞凋亡。探讨肝移植过程中NF κ B活化的作用；利用腺病毒介导的基因转移在供体肝脏中表达I κ B α超抑制因子。nf - κ B抑制导致移植3小时后血清丙氨酸转氨酶水平升高。此外，NF-kappa B的阻断导致组织学组织损伤增加，肝末端脱氧核糖核苷酸转移酶介导的脱氧尿苷三磷酸缺口端标记（TUNEL）染色增加，提示凋亡，这些结果表明NF-kappa B的激活在移植肝中具有保护作用。版权所有(C) 1999年由美国肝病研究协会。
Reperfusion after liver transplantation results in the induction of tumor necrosis factor-alpha (TNF alpha) as well as activation of the stress-associated signaling proteins, c-Jun N-terminal kinase (JNK), activating protein-1 (AP-1), and nuclear factor-kappa B (NF-kappa B), To test the hypothesis that Kupffer cells are involved in the activation of signal transduction cascades during rat liver transplantation, Kupffer cells were depleted from donor liver using gadolinium chloride (GdCl3), and then the activation of JNK, AP-1, and NF-kappa B were assessed after transplantation. The results showed that GdCl3 treatment did not. inhibit the activation of these stress signals, although transplanted livers were depleted of Kupffer cells and partially protected; from reperfusion injury. Interleukin-6 (IL-6) and IL-10 messenger RNAs (mRNAs) were induced by transplantation, and the induction was suppressed by Kupffer cell depletion. The induction of TNF alpha mRNA and serum protein during liver transplantation was unaffected by GdCl3. These results show that Kupffer cells are not a major source of TNF alpha production after liver transplantation and that stress-signaling protein activation occurs independently of Kupffer cells. Transplantation strongly activates the transcription factor NF-kappa B, which blocks TNF alpha-mediated apoptosis in hepatocytes in vitro. To assess the role of NF kappa B activation during liver transplantation; the I kappa B alpha superrepressor was expressed in donor livers using adenoviral-mediated gene transfer. Inhibition of NF-kappa B resulted in increased serum alanine aminotransferase levels after 3 hours of transplantation. In addition, the blockade of NF-kappa B resulted in increased histological tissue injury and increased hepatic terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining, indicating apoptosis, These results show that NF-kappa B activation has a protective role in the transplanted liver. Copyright (C) 1999 by the American Association for the Study of Liver Diseases.