Interleukin-1 Receptor Antagonist Has a Novel Function in the Regulation of Matrix Metalloproteinase-13 Expression.
Interleukin-1 Receptor Antagonist Has a Novel Function in the Regulation of Matrix Metalloproteinase-13 Expression.
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DOI：
10.1371/journal.pone.0140942
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Mitani A
中科院分区：
文献类型：
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作者：
Goto H;Ishihara Y;Kikuchi T;Izawa A;Ozeki N;Okabe E;Kamiya Y;Ozawa Y;Mizutani H;Yamamoto G;Mogi M;Nakata K;Maeda H;Noguchi T;Mitani A
白细胞介素-1受体拮抗剂（IL-1 Ra）是IL-1家族成员，其结合IL-1受体但不诱导任何细胞内信号传导。我们讨论了IL-1 Ra是否具有调节细胞外基质或粘附分子的新功能。聚合酶链反应阵列分析显示，与对照相比，IL-1 Ra siRNA转染的Ca 9 -22人口腔鳞状上皮癌细胞的基质金属蛋白酶13（MMP-13）mRNA表达增加约5倍。事实上，在IL-1 Ra siRNA转染的Ca 9 -22细胞系中，MMP-13 mRNA和蛋白表达及其活性均显著高于对照组。IL-1 Ra siRNA处理导致MMP-13表达强烈升高，而加入rhIL-1 Ra（40 ng/ml）抑制MMP-13表达，表明IL-1 Ra对MMP-13诱导具有特异性作用。IL-1 Ra siRNA能有效抑制IL-1α的表达。IL-1 Ra siRNA转染的细胞MMP-13 mRNA表达与抗IL-1α或抗IL-1β抗体处理的细胞MMP-13 mRNA表达无显著差异。这些结果表明，持续供应IL-1对IL-1 Ra siRNA诱导MMP-13没有影响。MMP-13在牙周组织中的组织学研究显示，在IL-1 Ra敲除（KO）小鼠的结合上皮细胞中的特异性定位。此外，用伴放线菌聚集杆菌感染建立实验性牙周炎模型，导致MMP-13沿着根尖结合上皮细胞主要定位。层粘连蛋白-5，这是由MMP-13降解，被发现在野生型小鼠的内部基底层，而IL-1 Ra KO小鼠的内部基底层没有显示出明显的层粘连蛋白-5定位。特别是，层粘连蛋白-5定位在感染A.伴随放线菌，表明IL-1 Ra的抑制导致降解层粘连蛋白-5的MMP-13的强烈诱导。总之，IL-1 Ra与MMP-13表达相关，并且在不干扰IL-1信号级联的情况下在这种调节中具有新的功能。
Interleukin-1 receptor antagonist (IL-1Ra) is an IL-1 family member, which binds to IL-1 receptors but does not induce any intracellular signaling. We addressed whether IL-1Ra has a novel function in regulation of the extracellular matrix or adhesion molecules. Polymerase chain reaction array analysis demonstrated a ~5-fold increase in matrix metalloproteinase 13 (MMP-13) mRNA expression of IL-1Ra siRNA-transfected Ca9-22 human oral squamous epithelial carcinoma cells compared with the control. In fact, MMP-13 mRNA and protein expression as well as its activity in IL-1Ra siRNA-transfected Ca9-22 cell lines were significantly higher than those in the control. IL-1Ra siRNA treatment resulted in strong elevation of MMP-13 expression, whereas addition of rhIL-1Ra (40 ng/ml) suppressed MMP-13 expression, suggesting that IL-1Ra had a specific effect on MMP-13 induction. IL-1Ra siRNA could potently suppress IL-1α. No significant difference was found between the MMP-13 mRNA expression of IL-1Ra siRNA-transfected cells and those treated with anti-IL-1α or anti-IL-1β antibodies. These results suggested that continuous supply of IL-1 had no effect on the induction of MMP-13 by IL-1Ra siRNA. Histopathological investigation of MMP-13 in periodontal tissue showed specific localization in the junctional epithelial cells of IL-1Ra knockout (KO) mice. Furthermore, infection with Aggregatibacter actinomycetemcomitans to establish an experimental periodontitis model resulted in predominant localization of MMP-13 along apical junctional epithelial cells. Laminin-5, which is degraded by MMP-13, was found in the internal basal lamina of wild-type mice, whereas the internal basal lamina of IL-1Ra KO mice did not show obvious laminin-5 localization. In particular, laminin-5 localization almost disappeared in the internal basal lamina of IL-1Ra KO mice infected with A. actinomycetemcomitans, suggesting that the suppression of IL-1Ra resulted in strong induction of MMP-13 that degraded laminin-5. In conclusion, IL-1Ra is associated with MMP-13 expression and has a novel function in such regulation without interference of the IL-1 signaling cascade.