Redox imbalance in Crohn's disease intestinal smooth muscle cells causes NF-kappaB-mediated spontaneous interleukin-8 secretion.
Redox imbalance in Crohn's disease intestinal smooth muscle cells causes NF-kappaB-mediated spontaneous interleukin-8 secretion.
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克罗恩病肠平滑肌细胞中的氧化还原失衡导致 NF-κB 介导的自发白细胞介素 8 分泌。
DOI：
10.1089/107999001750277826
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Fowler3rd,AA
中科院分区：
文献类型：
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作者：
Natarajan,R;Ghosh,S;Fisher,BJ;Diegelmann,RF;Willey,A;Walsh,S;Graham,MF;Fowler3rd,AA
白细胞介素8(IL-8)是一种由损伤部位的细胞分泌的趋化因子，最近被认为与克罗恩病的发病有关。然而，克罗恩病患者肠道IL-8自发转录增强的发病机制尚不明确。虽然IL-8主要由中性粒细胞、巨噬细胞以及内皮和上皮细胞分泌，但我们观察到间充质细胞参与了炎症过程。从克罗恩病(CDISM)患者回肠分离并培养的平滑肌细胞株与正常人(NHISM)的肠平滑肌细胞相比，具有自发转录和分泌IL-8的能力。此外，IL-8启动子报告结构的瞬时转染实验、Western印迹分析和凝胶迁移率改变分析表明，CDISM细胞的IL-8转录与氧化剂敏感的转录因子NF-κB的显著自发激活有关。最后，我们在这里报告CDISM细胞表现出显著的氧化还原平衡改变。抗氧化剂吡咯烷二硫代氨基甲酸酯通过抑制NF-κB与其在IL-8启动子上的同源位点的结合来恢复氧化还原平衡。这些发现表明，氧化还原平衡的恢复可能为克罗恩病的治疗干预带来希望。
Interleukin-8 (IL-8), a chemokine secreted by cells at injury sites, has recently been recognized as involved in the pathogenesis of Crohn's disease. However, the pathogenesis of enhanced spontaneous transcription of IL-8 by the bowel in patients with Crohn's disease is undefined. Although IL-8 is secreted primarily by neutrophils, macrophages, and endothelial and epithelial cells, we observed the involvement of mesenchymal cells in the inflammatory process. A smooth muscle cell line isolated from the ileum of a patient with Crohn's disease (CDISM) and maintained in culture exhibited spontaneous transcription and secretion of IL-8 when compared with intestinal smooth muscle cells obtained from a normal subject (NHISM). Furthermore, IL-8 transcription from CDISM cells was associated with remarkable spontaneous activation of the oxidant-sensitive transcription factor NF-κB, as assessed by transient transfection assays with an IL-8 promoter reporter construct, Western blot analysis, and electrophoretic mobility shift assays (EMSA). Finally, we report here that CDISM cells exhibit significantly altered redox balance. The antioxidant pyrrolidine dithiocarbamate (PDTC) restored the redox equilibrium by mechanisms that inhibit binding of NF-κB to its cognate site on the IL-8 promoter. These findings suggest that restoration of the redox balance could hold promise for therapeutic intervention in Crohn's disease.