CX3CL1 (Fractalkine): A Signpost for Biliary Inflammation in Primary Biliary Cirrhosis
CX3CL1 (Fractalkine): A Signpost for Biliary Inflammation in Primary Biliary Cirrhosis
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DOI：
10.1002/hep.23318
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发表时间：
2010-02-01
期刊：
影响因子：
13.5
通讯作者：
Akashi, Koichi
中科院分区：
文献类型：
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作者：
Shimoda, Shinji;Harada, Kenichi;Akashi, Koichi
原发性胆汁性肝硬变(PBC)治疗的改进可能依赖于对决定单个核细胞重新聚集到小叶内胆管的机制的剖析，包括趋化因子黏附分子CX3CL1(Fractalkine)的作用。我们认为，肝内胆管上皮细胞(BECs)、内皮细胞(ECs)、肝窦之间存在着独特的相互作用。内皮炎性细胞(LSECs)和肝脏浸润性单个核细胞(ILMCs)，这种相互作用将在一定程度上决定胆汁特异性炎症反应。为了解决这一问题，我们研究了移植前PBC患者和因病毒感染引起的炎症性肝病患者的新鲜移植肝(疾病对照)和来自离散肝肿瘤患者的活检材料(正常对照)。利用这一临床材料，我们分离和刺激了BECs、ECs、LSECs和LMCs，并使用了一组Toll样受体配体。我们还研究了这些细胞群与LMCs在黏附能力和产生肿瘤坏死因子α(TNF-α)方面的相互作用。最后，我们使用新鲜的活检样本，分别使用针对CD68或CD154的单抗、单核/巨噬细胞标志物和激活的T细胞来评估肝内胆管周围的单核细胞。结论：无论来源于PBC还是病毒性肝炎，ECs、LSECs和BECs都有共同的特性，但也有显著的差异，特别是在PBC中LMCs黏附ECs和BECs并产生肿瘤坏死因子-α的能力；这些特性与BEC从PBC肝脏产生CX3CL1的增加有关。本文定义的过程提示了治疗胆道特异性炎症的潜在的新的生物疗法。(《肝病》2010；51：567-575。)
Improvements in the treatment of primary biliary cirrhosis (PBC) may depend upon dissection of mechanisms that determine recruitment of mononuclear cells to intralobular bile ducts, including the role of the chemokine-adhesion molecule CX3CL1 (fractalkine). We submit that there are unique interactions between intrahepatic biliary epithelial cells (BECs), endothelial cells (ECs), liver sinusoidal. endothetial cells (LSECs), and liver-infiltrating mononuclear cells (ILMCs), and that such interactions will in part dictate the biliary specific inflammatory response. To address this, we studied fresh explanted livers from pretransplantation patients with PBC and with inflammatory liver disease due to viral infection (disease controls) and biopsy material from patients with a discrete liver tumor (normal controls). Using this clinical material, we isolated and stimulated BECs, ECs, LSECs, and LMCs with a panel of Toll-like receptor ligands. We also studied the interactions of these cell populations with LMCs with respect to adhesion capability and production of tumor necrosis factor alpha (TNF-alpha). Finally, we used fresh biopsy samples to evaluate mononuclear cells around intrahepatic biliary ductules using monoclonal antibodies specific to CD68 or CD154, markers for monocytes/macrophagcs, and activated T cells, respectively. Conclusion: There are common properties of ECs, LSECs, and BECs, whether derived from PBC or viral hepatitis, but there are also significant differences, particularly in the potential in PBC for LMCs to adhere to ECs and BECs and to produce TNF-alpha; such properties were associated with augmented CX3CL1 production by BEC from PBC liver. The processes defined herein suggest potential novel biotherapies for biliary specific inflammation. (HEPATOLOGY 2010;51:567-575.)