Soluble biglycan induces the production of ICAM-1 and MCP-1 in human aortic valve interstitial cells through TLR2/4 and the ERK1/2 pathway.
Soluble biglycan induces the production of ICAM-1 and MCP-1 in human aortic valve interstitial cells through TLR2/4 and the ERK1/2 pathway.
复制标题
DOI：
10.1007/s00011-014-0743-3
复制
发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Meng X
中科院分区：
文献类型：
--
作者：
Song R;Ao L;Zhao KS;Zheng D;Venardos N;Fullerton DA;Meng X
钙化性主动脉瓣病变的特征之一是瓣膜组织单核细胞浸润。主动脉瓣间质细胞（AVIC）的炎症反应在瓣膜炎症中起重要作用。然而，目前还不清楚是什么引起了中航工业的炎症反应。在患病的主动脉瓣叶中发现双糖链蛋白聚糖的积聚。可溶性双糖蛋白聚糖可以作为一种与巨噬细胞相关的分子模式来诱导培养的巨噬细胞中促炎介质的产生。我们检验了可溶性双糖蛋白聚糖诱导AVIC产生促炎介质的假设，该促炎介质通过Toll样受体（TLR）依赖性信号传导途径参与单核细胞浸润。在biglycan刺激之前，用特异性siRNA和针对TLR 2或TLR 4的中和抗体处理从正常主动脉瓣小叶分离的人AVIC。检测细胞间粘附分子-1（ICAM-1）和单核细胞趋化蛋白-1（MCP-1）的表达。为了确定所涉及的信号通路，分析ERK 1/2和p38 MAPK的磷酸化，并应用ERK 1/2和p38 MAPK的特异性抑制剂。可溶性双糖蛋白聚糖诱导人AVIC中ICAM-1表达和MCP-1释放，但对IL-6释放无影响。TLR4的阻断和敲低降低了双糖链蛋白聚糖诱导的ICAM-1和MCP-1的产生，而TLR2的敲低和中和导致对炎症反应的更大抑制。双糖蛋白聚糖诱导ERK 1/2和p38 MAPK的磷酸化，但ICAM-1和MCP-1的产生仅通过抑制ERK 1/2途径而减少。此外，抑制ERK 1/2减弱双糖蛋白聚糖处理后NF-κ B活化。可溶性双糖蛋白聚糖通过TLR2和TLR4诱导人AVIC中ICAM-1和MCP-1的表达，并且需要ERK 1/2通路的激活。可溶性双糖蛋白聚糖诱导的AVIC炎症反应可能参与钙化性主动脉瓣疾病相关慢性炎症机制。
Mononuclear cell infiltration in valvular tissue is one of the characteristics in calcific aortic valve disease. The inflammatory responses of aortic valve interstitial cells (AVICs) play an important role in valvular inflammation. However, it remains unclear what may evoke AVIC inflammatory responses. Accumulation of biglycan has been found in diseased aortic valve leaflets. Soluble biglycan can function as a danger-associated molecular pattern to induce the production of pro-inflammatory mediators in cultured macrophages. We tested the hypothesis that soluble biglycan induces AVIC production of pro-inflammatory mediators involved in mononuclear cell infiltration through Toll-like receptor (TLR)-dependent signaling pathways. Human AVICs isolated from normal aortic valve leaflets were treated with specific siRNA and neutralizing antibody against TLR2 or TLR4 before biglycan stimulation. The production of ICAM-1 and MCP-1 were assessed. To determine the signaling pathway involved, phosphorylation of ERK1/2 and p38 MAPK was analyzed, and specific inhibitors of ERK1/2 and p38 MAPK were applied. Soluble biglycan induced ICAM-1 expression and MCP-1 release in human AVICs, but had no effect on IL-6 release. TLR4 blockade and knockdown reduced ICAM-1 and MCP-1 production induced by biglycan, while knockdown and neutralization of TLR2 resulted in greater suppression of the inflammatory responses. Biglycan induced the phosphorylation of ERK1/2 and p38 MAPK, but ICAM-1 and MCP-1 production was reduced only by inhibition of the ERK1/2 pathway. Further, inhibition of ERK1/2 attenuated NF-κB activation following biglycan treatment. Soluble biglycan induces the expression of ICAM-1 and MCP-1 in human AVICs through TLR2 and TLR4, and requires activation of the ERK1/2 pathway. AVIC inflammatory responses induced by soluble biglycan may contribute to the mechanism of chronic inflammation associated with calcific aortic valve disease.