CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver.
CX3CL1/fractalkine shedding by human hepatic stellate cells: contribution to chronic inflammation in the liver.
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DOI：
10.1111/j.1582-4934.2009.00787.x
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发表时间：
2009-08
影响因子：
5.3
通讯作者：
Théret N
中科院分区：
文献类型：
--
作者：
Bourd-Boittin K;Basset L;Bonnier D;L'helgoualc'h A;Samson M;Théret N
趋化因子是调节肝纤维化的炎症介质，肝纤维化是慢性炎症性肝病的共同特征。CX3CL1/Fractalkine是一种膜相关趋化因子，需要分步处理才能发挥趋化活性，最近被认为与肝脏疾病有关。在这里，我们研究了CX3CL1在受损肝脏中释放可溶性趋化性多肽的潜在脱落活性。我们发现，在慢性肝病患者中，脱落酶ADAM10和ADAM17的表达增加，这与肝纤维化的严重程度有关。我们证明肝星状细胞是ADAM10和ADAM17的重要来源，用炎性细胞因子干扰素-γ处理可诱导CX3CL1的表达和可溶性多肽的释放。这种释放被金属蛋白酶抑制剂batimastat抑制；然而，ADAM10/ADAM17抑制剂GW280264X仅部分影响脱落活性。通过使用选择性组织金属蛋白酶抑制剂和过表达分析，我们发现CX3CL1主要由基质金属蛋白酶-2(MMP2)处理，这是一种由HSC高表达的金属蛋白酶。我们进一步证明，从刺激的HSC释放的CX3CL1可溶性多肽在体外诱导了依赖CX3CR1的信号通路的激活，并促进了单核细胞的趋化作用。结论：活化的HSC合成的ADAM10、ADAM17和MMP2介导CX3CL1趋化多肽的释放和释放，从而促进慢性肝病HSC的炎症细胞募集和旁分泌刺激。
Chemokines are the inflammatory mediators that modulate liver fibrosis, a common feature of chronic inflammatory liver diseases. CX3CL1/fractalkine is a membrane-associated chemokine that requires step processing for chemotactic activity and has been recently implicated in liver disease. Here, we investigated the potential shedding activities involved in the release of the soluble chemotactic peptides from CX3CL1 in the injured liver. We showed an increased expression of the sheddases ADAM10 and ADAM17 in patients with chronic liver diseases that was associated with the severity of liver fibrosis. We demonstrated that hepatic stellate cells (HSC) were an important source of ADAM10 and ADAM17 and that treatment with the inflammatory cytokine inter-feron-γ induced the expression of CX3CL1 and release of soluble peptides. This release was inhibited by the metalloproteinase inhibitor batimastat; however, ADAM10/ADAM17 inhibitor GW280264X only partially affected shedding activity. By using selective tissue metalloprotease inhibitors and overexpression analyses, we showed that CX3CL1 was mainly processed by matrix metalloproteinase (MMP)-2, a metalloprotease highly expressed by HSC. We further demonstrated that the CX3CL1 soluble peptides released from stimulated HSC induced the activation of the CX3CR1-dependent signalling pathway and promoted chemoattraction of monocytes in vitro. We conclude that ADAM10, ADAM17 and MMP-2 synthesized by activated HSC mediate CX3CL1 shedding and release of chemotactic peptides, thereby facilitating recruitment of inflammatory cells and paracrine stimulation of HSC in chronic liver diseases.
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