Bacterial lipopolysaccharide and antimicrobial LL-37 enhance ICAM-1 expression and NF-κB p65 phosphorylation in senescent endothelial cells
Bacterial lipopolysaccharide and antimicrobial LL-37 enhance ICAM-1 expression and NF-κB p65 phosphorylation in senescent endothelial cells
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DOI：
10.3892/ijmm.2019.4294
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发表时间：
2019-10-01
影响因子：
5.4
通讯作者：
Nagaoka, Isao
中科院分区：
文献类型：
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作者：
Suzuki, Kaori;Ohkuma, Mari;Nagaoka, Isao
细胞衰老与促炎表型的诱导相关。值得注意的是，在动脉粥样硬化病变部位检测到衰老内皮细胞，表明衰老内皮细胞参与动脉粥样硬化形成。此外，细菌感染已被推测有助于动脉粥样硬化的发病机制。本研究使用连续传代的人内皮细胞，研究革兰氏阴性细菌脂多糖（LPS）和LL-37（cathelicidin家族的人抗菌肽）对衰老内皮细胞的影响。结果表明，衰老的内皮细胞表现出基础的促炎表型，如通过较高的细胞间粘附分子-1（ICAM-1）表达和NF-κ B p65磷酸化，与非衰老细胞相比。此外，与非衰老细胞相比，暴露于LPS和LL-37进一步增强了衰老内皮细胞中ICAM-1的表达。值得注意的是，NF-κ B p65通路在用LPS和LL-37刺激的衰老内皮细胞中被更多地激活。此外，LPS和LL-37的受体[分别为Toll样受体4（TLR 4）和嘌呤能受体P2 X7（P2 X7）]的表达水平在衰老内皮细胞中上调。这些观察结果表明，LPS和LL-37可能通过上调TLR 4和P2 X 7增强衰老内皮细胞中ICAM-1表达和NF-κ B p65活化。因此，衰老的内皮细胞可能通过基础促炎表型和增强的对致动脉粥样硬化因子（包括LPS和LL-37）的炎症反应而促成动脉粥样硬化的发病机制。
Cellular senescence is associated with the induction of a proinflammatory phenotype. Notably, senescent endothelial cells are detected at the sites of atherosclerotic lesions, suggesting the involvement of senescent endothelial cells in atherogenesis. Moreover, bacterial infection has been speculated to contribute to the pathogenesis of atherosclerosis. The present study investigated the effects of Gram-negative bacterial lipopolysaccharide (LPS) and LL-37 (a human antimicrobial peptide of the cathelicidin family), on senescent endothelial cells, using serially passaged human endothelial cells. The results indicated that senescent endothelial cells exhibited the basal proinflammatory phenotype, as evidenced by higher intercellular adhesion molecule-1 (ICAM-1) expression and NF-kappa B p65 phosphorylation, compared with non-senescent cells. Additionally, exposure to LPS and LL-37 further enhanced the expression of ICAM-1 in senescent endothelial cells, compared with non-senescent cells. Of note, the NF-kappa B p65 pathway was more activated in senescent endothelial cells stimulated with LPS and LL-37. Furthermore, the expression levels of the receptors for LPS and LL-37 [toll-like receptor 4 (TLR4) and purinergic receptor P2X 7 (P2X7), respectively] were upregulated in senescent endothelial cells. These observations indicated that LPS and LL-37 enhanced the ICAM-1 expression and NF-kappa B p65 activation in senescent endothelial cells, potentially via the upregulated TLR4 and P2X7. Thus, senescent endothelial cells may contribute to the pathogenesis of atherosclerosis via the basal proinflammatory phenotype and the enhanced inflammatory responses against atherogenic factors, including LPS and LL-37.