Inhibition of cellular and systemic inflammation cues in human bronchial epithelial cells by melanocortin-related peptides: mechanism of KPV action and a role for MC3R agonists.
Inhibition of cellular and systemic inflammation cues in human bronchial epithelial cells by melanocortin-related peptides: mechanism of KPV action and a role for MC3R agonists.
复制标题
黑皮质素相关肽对人支气管上皮细胞中细胞和全身炎症信号的抑制：KPV 作用机制和 MC3R 激动剂的作用。
DOI：
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
S. Land
中科院分区：
文献类型：
--
作者：
S. Land
背景/目的
哮喘等炎症性疾病中来自气道上皮的趋化因子信号调节巨噬细胞向肺的募集。本研究探讨了α-黑素细胞刺激素衍生的三肽KPV和气道上皮中显性黑皮质素受体（MC 3R）激动剂γ-黑素细胞刺激素（γ-MSH）抑制永生化人支气管气道上皮炎症的机制。
方法
在永生化的人支气管上皮细胞（16 HBE 14 o-）中测量TNFα和鼻合胞病毒（RSV）诱发的核因子-κB（NFκB）信号对KPV和γMSH的应答。分别通过NFκB报告基因和趋化因子（IL 8，eotaxin）分泌来测量细胞和全身炎症信号。
结果
KPV和γMSH可剂量依赖性地抑制NFκB、MMP-9活性、IL-8和Eotaxin的分泌。KPV效应与其核输入、IκBα稳定和抑制YFP标记的p65 RelA核转位有关。竞争性分析显示KPV与p65 RelA上的Imp-α3结合位点之间存在相互作用，这可能涉及对importin-α armadillo结构域7和8的阻断。相反，γMSH抗炎作用需要MC 3 R，其在体内沿呼吸树沿着长度分布的上皮中顶端表达。
结论
KPV和γMSH分别通过抑制p65 RelA核输入和激活上皮MC 3 R来抑制气道上皮中的NFκB信号传导。因此，黑皮质素肽为靶向肺部疾病中的气道炎症提供了强大的机制。
BACKGROUND/AIMS
Chemokine signaling from airway epithelium regulates macrophage recruitment to the lung in inflammatory diseases such as asthma. This study investigates the mechanism by which the α-melanocyte stimulating hormone-derived tripeptide, KPV, and the agonist of the dominant melanocortin receptor in airway epithelium (MC3R), γ-melanocyte stimulating hormone (γ-MSH), suppress inflammation in immortalised human bronchial airway epithelium.
METHODS
TNFα and rhino syncitial virus (RSV)-evoked nuclear factor-κB (NFκB) signaling was measured in immortalised human bronchial epithelial cells (16HBE14o-) in response to KPV and γMSH. Cellular and systemic inflammatory signaling was measured by NFκB reporter gene and chemokine (IL8, eotaxin) secretion, respectively.
RESULTS
KPV and γMSH evoked a dose-dependent inhibition of NFκB, matrix metalloproteinase-9 activity, IL8 and eotaxin secretion. The KPV effect was associated with its nuclear import, IκBα stabilisation and suppressed nuclear translocation of YFP-tagged p65RelA. Competition assays revealed an interaction between KPV and the Imp-α3 binding site on p65RelA which may involve blockade of the importin-α armadillo domain 7 and 8. In contrast, the γMSH anti-inflammatory effect required MC3R whose apical expression occurred in epithelium distributed along the length of the respiratory tree in vivo.
CONCLUSION
KPV and γMSH respectively suppress NFκB signalling in airway epithelium by: i) inhibition of p65RelA nuclear import and, ii) epithelial MC3R activation. Melanocortin peptides therefore provide a robust mechanism for targeting airway inflammation in lung disease.
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DOI：
10.1016/s0021-9258(19)38926-4
发表时间：
1990-05
期刊：
The Journal of biological chemistry
影响因子：
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作者：
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DOI：
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发表时间：
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期刊：
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影响因子：
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影响因子：
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影响因子：
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DOI：
10.1165/ajrcmb.10.1.7507342
发表时间：
1994-01-01
影响因子：
6.4
作者：
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GRUENERT, DC