脂多糖通过 TACE/TGF-α/EGFR 通路增加人肝内胆管上皮细胞的 MUC5AC。
LPS increases MUC5AC by TACE/TGF-α/EGFR pathway in human intrahepatic biliary epithelial cell.
机构信息
Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, No. 29 Gaotanyan Street, Shapingba District, Chongqing 400038, China ; The 306th Hospital of PLA, No. 9 Anxiang Road (N), Chaoyang District, Beijing 100101, China.
出版信息
Biomed Res Int. 2013;2013:165715. doi: 10.1155/2013/165715. Epub 2013 Aug 20.
BACKGROUND
Mucin 5AC (MUC5AC) overproduction plays important roles in stone formation and recurrence of hepatolithiasis. We aim to investigate the involved mechanism and the potential target to block this process.
METHODS
42 bile duct samples from hepatolithiasis and 15 normal bile duct samples from hemangioma patients were collected for detecting MUC5AC expression by immunohistochemistry. MUC5AC and phosphoepidermal growth factor receptor (pEGFR) expressions in human intrahepatic biliary epithelial cells (HIBECs) cultured with or without lipopolysaccharide (LPS) were detected by real-time PCR and western blot analysis. Transforming growth factor-α (TGF-α) secretion in HIBECs was detected by ELISA.
RESULTS
MUC5AC was overexpressed in bile ducts of hepatolithiasis samples compared with bile ducts from hemangioma samples. LPS upregulated MUC5AC expression in HIBECs. LPS promoted EGFR activation, and inhibiting EGFR activation by AG1478 significantly decreased LPS-induced MUC5AC overexpression in HIBECs. Moreover, LPS increased TGF-α secretion, and inhibiting tumor necrosis factor-α converting enzyme (TACE), which has been implicated in ectodomain cleavage of TGF-α, significantly inhibited LPS-induced EGFR activation and subsequent MUC5AC overexpression in HIBECs.
CONCLUSION
Our results suggested that LPS increases MUC5AC expression through the TACE/TGF-α/EGFR pathway in HIBECs. This new finding might give light to the prevention of stone formation and recurrence of hepatolithiasis.
背景
黏蛋白 5AC（MUC5AC）过度表达在胆石形成和胆石病复发中起重要作用。我们旨在研究涉及的机制和潜在的靶点来阻断这一过程。
方法
收集 42 例胆石病胆管组织标本和 15 例肝血管瘤患者正常胆管组织标本，采用免疫组织化学法检测 MUC5AC 表达。用脂多糖（LPS）刺激人肝内胆管上皮细胞（HIBEC），通过实时 PCR 和 Western blot 分析检测 MUC5AC 和磷酸化表皮生长因子受体（pEGFR）的表达。用 ELISA 法检测 HIBEC 中转化生长因子-α（TGF-α）的分泌。
结果
与肝血管瘤胆管组织相比，胆石病胆管组织中 MUC5AC 过度表达。LPS 可上调 HIBEC 中 MUC5AC 的表达。LPS 可促进 EGFR 激活，用 AG1478 抑制 EGFR 激活可显著降低 LPS 诱导的 HIBEC 中 MUC5AC 的过度表达。此外，LPS 可增加 TGF-α 的分泌，而抑制肿瘤坏死因子-α转换酶（TACE），TACE 可使 TGF-α 的胞外结构域裂解，可显著抑制 LPS 诱导的 EGFR 激活及随后 HIBEC 中 MUC5AC 的过度表达。
结论
我们的研究结果表明，LPS 通过 HIBEC 中的 TACE/TGF-α/EGFR 途径增加 MUC5AC 的表达。这一新发现可能为胆石形成和胆石病复发的预防提供新的思路。
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