Expression of leukemia inhibitory factor (LIF) and its receptor gp190 in human liver and in cultured human liver myofibroblasts. Cloning of new isoforms of LIF mRNA.
Expression of leukemia inhibitory factor (LIF) and its receptor gp190 in human liver and in cultured human liver myofibroblasts. Cloning of new isoforms of LIF mRNA.
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DOI：
10.1186/1476-5926-3-10
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发表时间：
2004-11-26
期刊：
影响因子：
--
通讯作者：
Rosenbaum, Jean
中科院分区：
文献类型：
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作者：
Hisaka, Toru;Desmouliere, Alexis;Rosenbaum, Jean
背景：细胞因子白血病抑制因子（LIF）通过与低亲和力LIF受体亚基gp190 （LIF- r）和gp130亚基组成的高亲和力受体结合，介导其生物学效应。LIF在肝脏中发挥着几种重要作用，然而，关于LIF在肝脏中的表达的数据很少。本研究的目的是检测LIF和LIF- r在人肝脏中的表达。结果：通过免疫组化分析，LIF表达在正常肝脏中几乎检测不到，但在肝硬化纤维间隔中很强，并且在与肌成纤维细胞相容的纺锤形细胞中发现。因此，ELISA和Northern blot结果显示，培养的人肝脏肌成纤维细胞表达高水平的LIF。生物实验表明，肌成纤维细胞衍生的LIF是完全活跃的。RT-PCR显示了lifd和M亚型的表达，以及由于选择性剪接删除外显子2而导致的lifd和lifm的低水平新变体。LIF受体的表达主要通过连续的正弦染色检测，在肝硬化中增强，提示内皮细胞和/或肝细胞标记。免疫组织化学、流式细胞术和STAT-3磷酸化检测均未发现肌成纤维细胞本身表达LIF受体的证据。白细胞介素-4的加入可下调培养的肌成纤维细胞的LIF分泌。结论：我们首次发现了LIF在人肝肌成纤维细胞中的表达，以及LIF mRNA的两种新亚型。肌成纤维细胞表达LIF及其受体在邻近细胞中的表达表明，人肝脏中存在潜在的LIF旁分泌环，可能在肝内炎症的调节中发挥作用。
BACKGROUND: The cytokine leukemia inhibitory factor (LIF) mediates its biological effects through binding to its high affinity receptor made of the low-affinity LIF receptor subunit gp190 (LIF-R) and the gp130 subunit. LIF exerts several important effects in the liver, however, data on liver expression of LIF are scarce. The aim of this study was to examine the expression of LIF and LIF-R in human liver. RESULTS: LIF expression, analyzed by immunohistochemistry, was barely detectable in normal liver but was strong within cirrhotic fibrous septa and was found in spindle-shaped cells compatible with myofibroblasts. Accordingly, cultured human liver myofibroblasts expressed high levels of LIF as shown by ELISA and Northern blot. Biological assay demonstrated that myofibroblast-derived LIF was fully active. RT-PCR showed expression of the LIF-D and M isoforms, and also of low levels of new variants of LIF-D and LIF-M resulting from deletion of exon 2 through alternative splicing. LIF receptor expression was detected mainly as a continuous sinusoidal staining that was enhanced in cirrhotic liver, suggestive of endothelial cell and/or hepatocyte labeling. Immunohistochemistry, flow cytometry and STAT-3 phosphorylation assays did not provide evidence for LIF receptor expression by myofibroblasts themselves. LIF secretion by cultured myofibroblasts was down regulated by the addition of interleukin-4. CONCLUSIONS: We show for the first time the expression of LIF in human liver myofibroblasts, as well as of two new isoforms of LIF mRNA. Expression of LIF by myofibroblasts and of its receptor by adjacent cells suggests a potential LIF paracrine loop in human liver that may play a role in the regulation of intra-hepatic inflammation.