Potential role of a series of lysine-/leucine-rich antimicrobial peptide in inhibiting lipopolysaccharide-induced inflammation
Potential role of a series of lysine-/leucine-rich antimicrobial peptide in inhibiting lipopolysaccharide-induced inflammation
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一系列富含赖氨酸/亮氨酸的抗菌肽在抑制脂多糖诱导的炎症中的潜在作用
DOI：
10.1042/bcj20180483
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发表时间：
2018-11-30
影响因子：
4.1
通讯作者：
Shang, Dejing
中科院分区：
文献类型：
--
作者：
Dong, Weibing;Zhu, Xin;Shang, Dejing
抗菌肽通过细胞膜渗透作用对细菌、包膜病毒、真菌和多种寄生虫具有广谱杀伤活性，并在与宿主细胞的相互作用中主要表现出免疫调节和抗感染功能。然而，其抗炎活性的机制仍有待阐明。L-K6是从中国林蛙皮肤分泌物中分离得到的temporin-1CEb类似物，对革兰氏阴性菌和革兰氏阳性菌具有广泛的抗菌活性。在这项研究中，L-K6及其类似物在脂多糖（LPS）刺激的人巨噬细胞U937细胞中的有效抗炎机制进行了评估。我们发现L-K6通过MyD 88依赖性通路中的两个下游信号组分抑制炎症因子的表达，包括丝裂原活化蛋白激酶（MAPK）和NF-κ B。（核因子）-κ B信号通路，但其类似物L-K5，其具有与L-K6相同的氨基酸序列但在-COOH末端没有Lys残基，仅抑制I-κ B和NF-κ B的磷酸化。重要的是，L-K6和L-K5通过独立的细胞膜破坏机制被U937细胞主动摄取，并最终定位于核周区域。U937细胞对L-K6的摄取过程是由内吞作用介导的，而对L-K5的摄取则是通过TLR 4的内吞作用进行的。我们的研究结果表明，L-K6可以中和LPS和解离LPS胶束，以抑制LPS触发促炎信号通路，并通过细胞内靶点部分抑制炎症反应。然而，L-K5可能主要通过细胞内报告分子抑制促炎反应以调节NF-κ B信号通路。
Antimicrobial peptides have broad-spectrum killing activities against bacteria, enveloped viruses, fungi and several parasites via cell membrane permeation and exhibit primarily immunomodulatory and anti-infective functions in their interactions with host cells. However, the mechanism underlying their anti-inflammatory activity remains to be elucidated. L-K6, an analog of temporin-1CEb isolated from the skin secretion of Rana chensinensis, has demonstrated a wide range of antimicrobial activities against gram-negative and gram-positive bacteria. In this study, the potent anti-inflammatory mechanism of L-K6 and its analogs in lipopolysaccharide (LPS)-stimulated human macrophage U937 cells were evaluated. We found that L-K6 suppressed the expression of inflammatory factors by two downstream signaling components in the MyD88-dependent pathway, including the mitogen-activated protein kinases (MAPKs) and the NF (nuclear factor)-kappa B signaling pathway, but its analog L-K5, which had the same amino acid sequence as L-K6 but no Lys residue at the -COOH terminal, only inhibited the phosphorylation of I-kappa B and NF-kappa B. Importantly, L-K6 and L-K5 were actively taken up by U937 cells through an independent cell membrane disruption mechanism and were eventually localized to the perinuclear region. The L-K6 uptake process was mediated by endocytosis, but L-K5 was specifically taken up by U937 cells via TLR4 endocytosis. Our results demonstrated that L-K6 can neutralize LPS and diassociate LPS micelles to inhibit LPS from triggering the proinflammatory signaling pathway, and by partially inhibiting inflammatory responses by the intracellular target. However, L-K5 may mainly inhibit proinflammatory responses by intracellular reporters to modulate the NF-kappa B signaling pathway.