IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-β receptor on hepatic stellate cells in a JNK-dependent manner.
IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-β receptor on hepatic stellate cells in a JNK-dependent manner.
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DOI：
10.4049/jimmunol.1400861
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发表时间：
2014-10-15
期刊：
影响因子：
--
通讯作者：
Shoukry NH
中科院分区：
文献类型：
--
作者：
Fabre T;Kared H;Friedman SL;Shoukry NH
肝星状细胞（hepatic stellate cells，HSC）的活化是肝纤维化发生的关键环节，其特征是细胞外基质（extracellular matrix，ECM）的产生和降解的改变。HSC的活化可以通过免疫细胞产生的细胞因子来调节。最近的报告表明促炎细胞因子IL-17 A参与了肝纤维化的进展。我们推测IL-17 A可能增强HSC的活化和这些细胞中纤维化信号的诱导。用增加剂量的IL-17 A刺激人HSC系LX2和原代人HSC，并分别与作为阳性和阴性对照的TGF-β和PBS处理的细胞进行比较。IL-17A单独不诱导HSC活化。然而，IL-17 A使HSC对次优剂量的TGF-β的作用敏感，如通过强烈诱导α-平滑肌肌动蛋白（α-SMA）、I型胶原（COL1A1）和基质金属蛋白酶组织抑制剂I（TIMP-I）基因表达和蛋白质产生所证实的。IL-17 A特异性上调刺激后TGF-β-RII的细胞表面表达。用IL-17 A预处理HSC增强了通过TGF-β-RII的信号传导，如通过响应于次优剂量的TGF-β刺激而增加的SMAD 2/3磷酸化所观察到的。IL-17 A诱导的HSC的这种增强的TGF-β反应是JNK依赖性的。我们的研究结果表明，IL-17 A通过激活JNK途径增强HSC对TGF-β的反应，从而具有新的促纤维化功能。IL-17 A通过上调和稳定TGF-β-RII发挥作用，导致SMAD 2/3信号传导增加。这些发现代表了免疫细胞因子和纤维化受体之间协同信号传导的新实例。
Activation of hepatic stellate cells (HSCs) is a key event in the initiation of liver fibrosis, characterized by enhanced extracellular matrix (ECM) production and altered degradation. Activation of HSCs can be modulated by cytokines produced by immune cells. Recent reports have implicated the pro-inflammatory cytokine IL-17A in liver fibrosis progression. We hypothesized that IL-17A may enhance activation of HSC and induction of the fibrogenic signals in these cells. The human HSC line LX2 and primary human HSCs were stimulated with increasing doses of IL-17A and compared to TGF-β and PBS-treated cells as positive and negative controls, respectively. IL-17A alone did not induce activation of HSC. However, IL-17A sensitized HSCs to the action of suboptimal doses of TGF-β as confirmed by strong induction of alpha-smooth muscle actin (α-SMA), collagen type I (COL1A1) and tissue inhibitor of matrix metalloproteinase I (TIMP-I) gene expression and protein production. IL-17A specifically upregulated the cell surface expression of TGF-β-RII following stimulation. Pretreatment of HSCs with IL-17A enhanced signaling through the TGF-β-RII as observed by increased phosphorylation of SMAD2/3 in response to stimulation with suboptimal doses of TGF-β. This enhanced TGF-β response of HSCs induced by IL-17A was JNK-dependent. Our results suggest a novel pro-fibrotic function for IL-17A by enhancing the response of HSCs to TGF-β through activation of the JNK pathway. IL-17A acts through upregulation and stabilization of the TGF-β-RII leading to increased SMAD2/3 signaling. These findings represent a novel example of cooperative signaling between an immune cytokine and a fibrogenic receptor.
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影响因子：
4.9
作者：
Brembilla NC;Montanari E;Truchetet ME;Raschi E;Meroni P;Chizzolini C
通讯作者：
Chizzolini C
DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
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影响因子：
5.6
作者：
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通讯作者：
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影响因子：
4.4
作者：
Bengsch, Bertram;Seigel, Bianca;Thimme, Robert
通讯作者：
Thimme, Robert