Proinflammatory effects of Tweak/Fn14 interactions in glomerular mesangial cells
Proinflammatory effects of Tweak/Fn14 interactions in glomerular mesangial cells
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DOI：
10.4049/jimmunol.176.3.1889
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发表时间：
2006-02-01
影响因子：
4.4
通讯作者：
Putterman, C
中科院分区：
文献类型：
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作者：
Campbell, S;Burkly, LC;Putterman, C
肿瘤坏死因子样弱诱导因子是肿瘤坏死因子配体超家族中的一个相对较新的成员。TWEEP对TWEEP受体Fn14的连接对成纤维细胞、滑膜细胞和内皮细胞有促炎作用。几种TWEEP诱导的细胞因子在肾脏疾病的发病机制中起重要作用；然而，TWEW是否能对肾脏细胞产生促炎作用尚不清楚。我们发现小鼠肾小球系膜细胞表达细胞表面TWINE受体。肾小球系膜细胞微调刺激后CCL2/MCP-1、CCL5/RANTES、CXCL10/干扰素-γ诱导蛋白10 kDa和CXCL1/Kc的表达呈剂量依赖性增加。诱导的趋化因子水平与肾小球系膜细胞暴露于强烈的促炎刺激，如肿瘤坏死因子-α+白介素1-β的水平相当。TWEE还上调了CXCL11/干扰素诱导的T细胞趋化因子CXCR5、粘膜寻址细胞黏附分子-1和VCAM-1的表达。TWEAM刺激系膜细胞后，Ikappa-B磷酸化水平增加，而Ikappa-B磷酸化抑制剂预处理可显著阻断趋化因子的诱导，提示在TWeak诱导的趋化因子分泌中，NF-kappa B信号通路被激活。重要的是，用Fn14缺陷小鼠的肾小球系膜细胞和野生型与Fn14缺陷小鼠体内注射TWINE证实了TWEK对肾细胞的促炎作用。最后，新型小鼠抗TWEAM抗体可阻止TWEK诱导的趋化因子分泌。结论：TWAKE可诱导肾小球系膜细胞分泌促炎趋化因子，提示TWAKE在肾损伤发病机制中具有重要作用。我们的结果支持抗体抑制TWEEP是治疗趋化因子依赖的炎症性肾病的一种潜在的新方法。
TNF-like weak inducer of apoptosis, or TWEAK, is a relatively new member of the TNF-ligand superfamily. Ligation of the TWEAK receptor Fn14 by TWEAK has proinflammatory effects on fibroblasts, synoviocytes, and endothelial cells. Several of the TWEAK-inducible cytokines are important in the pathogenesis of kidney diseases; however, whether TWEAK can induce a proinflammatory effect on kidney cells is not known. We found that murine mesangial cells express cell surface TWEAK receptor. TWEAK stimulation of mesangial cells led to a dose-dependent increase in CCL2/MCP-1, CCL5/RANTES, CXCL10/IFN-gamma-induced protein 10 kDa, and CXCL1/KC. The induced levels of chemokines were comparable to those found following mesangial cell exposure to potent proinflammatory stimuli such as TNF-alpha + IL-1 beta. CXCL11/interferon-inducible T cell a chemoattractant, CXCR5, mucosal addressin cell adhesion molecule-1, and VCAM-1 were up-regulated by TWEAK as well. TWEAK stimulation of mesangial cells resulted in an increase in phosphorylated I kappa-B, while pretreatment with an I kappa-B phosphorylation inhibitor significantly blocked chemokine induction, implicating activation of the NF-kappa B signaling pathway in TWEAK-induced chemokine secretion. Importantly, the Fn14-mediated proinflammatory effects of TWEAK on kidney cells were confirmed using mesangial cells derived from Fn14-deficient mice and by injection in vivo of TWEAK into wild-type vs Fn14-deficient mice. Finally, TWEAK-induced chemokine secretion was prevented by treatment with novel murine anti-TWEAK Abs. We conclude that TWEAK induces mesangial cells to secrete proinflammatory chemokines, suggesting a prominent role for TWEAK in the pathogenesis of renal injury. Our results support Ab inhibition of TWEAK as a potential new approach for the treatment of chemokine-dependent inflammatory kidney diseases.