NF-kappa B activation and modulation in hepatic macrophages during cholestatic injury
NF-kappa B activation and modulation in hepatic macrophages during cholestatic injury
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DOI：
10.1006/jsre.1997.5172
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发表时间：
1997-10-01
影响因子：
2.2
通讯作者：
Tracy, TF
中科院分区：
文献类型：
--
作者：
Fox, ES;Kim, JC;Tracy, TF
胆汁淤积性肝损伤诱导了肝脏巨噬细胞活化后的炎症反应。在肝损伤过程中，在这些巨噬细胞中发现转录因子NF-κ B的组成性激活。由于NF-κ B活化已被证明在炎症过程中具有关键作用，因此在本研究中检查了抗氧化剂α-生育酚琥珀酸酯和糖皮质激素地塞米松对NF-κ B活化的调节作用。雄性Sprague道利大鼠经历2-7天的胆总管分离和结扎（CBDL）或假剖腹术。通过胶原酶Pronase灌注分离肝巨噬细胞，并通过离心淘洗纯化。通过电泳迁移率变动分析和ELISA测定活化。我们确定，NF-κ B B活化损伤的肝巨噬细胞只能抑制地塞米松。地塞米松介导的NF-κ B活化抑制需要一种调节蛋白的合成，因为放线菌酮处理的细胞对其作用具有抗性。此外，地塞米松处理的肝巨噬细胞显示I κ B-α mRNA的稳态水平升高，表明I κ B-α作为潜在的调节介质的作用。与组成性转录激活一致，我们显示TNF-α从损伤的肝巨噬细胞中组成性分泌，其可以被地塞米松抑制。这些数据首次显示，在肝损伤的生物学显著模型中，关键炎性转录因子NF-κ B和细胞因子TNF-α的组成性活化。这些结果支持一种方法，重点是NF-κ B/I κ B-α途径作为肝损伤期间治疗干预的关键靶点，并考虑可能的类固醇为基础的治疗。(C)北京：科学出版社.
Cholestatic liver injury induces an inflammatory response that follows the activation of hepatic macrophages. Constitutive activation of the transcription factor, NF-kappa B, was found in these macrophages over the course of hepatic injury. Since NF-kappa B activation has been shown to have a key role in the inflammatory process, the modulatory effects of the antioxidant, alpha-tocopherol succinate, and the glucocorticoid, dexamethasone, on NF-kappa B activation were examined in this study, Male Sprague Dawley rats underwent 2-7 days of common bile duct division and ligation (CBDL) or sham laparotomy. Hepatic macrophages were isolated by collagenase Pronase perfusion and purified by centrifugal elutriation. Activation was determined by electrophoretic mobility shift assay and ELISA. We determined that NF-kappa B activation in injured hepatic macrophages could only be inhibited by dexamethasone. Dexamethasone-mediated inhibition of NF-kappa B activation required the synthesis of a regulatory protein since cycloheximide treated cells were resistant to its effects. Furthermore, dexamethasone-treated hepatic macrophages showed elevated steady-state levels of I kappa B-alpha mRNA, suggesting the role of I kappa B-alpha as a potential regulatory mediator. Consistent with constitutive transcriptional activation we showed constitutive secretion of TNF-alpha from injured hepatic macrophages which could be inhibited by dexamethasone. These data show for the first time, in a biologically significant model of hepatic injury, constitutive activation of the key inflammatory transcription factor NF-kappa B and cytokine TNF-alpha. These results support an approach focused on the NF-kappa B/I kappa B-alpha pathway as a critical target for therapeutic intervention during hepatic injury, and the consideration of possible steroid-based therapies. (C) 1997 Academic Press.