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肝素抗炎作用的分子机制。

Molecular Mechanism of the Anti-Inflammatory Action of Heparin.

机构信息

Faculty of Physics, Sofia University "St. Kl. Ohridski", 5, James Bourchier Blvd, 1164 Sofia, Bulgaria.

Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, 9, Acad. G. Bonchev Str., 1113 Sofia, Bulgaria.

出版信息

Int J Mol Sci. 2021 Oct 3;22(19):10730. doi: 10.3390/ijms221910730.

DOI:10.3390/ijms221910730
PMID:34639073
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8509397/
Abstract

Our objective is to reveal the molecular mechanism of the anti-inflammatory action of low-molecular-weight heparin (LMWH) based on its influence on the activity of two key cytokines, IFNγ and IL-6. The mechanism of heparin binding to IFNγ and IL-6 and the resulting inhibition of their activity were studied by means of extensive molecular-dynamics simulations. The effect of LMWH on IFNγ signalling inside stimulated WISH cells was investigated by measuring its antiproliferative activity and the translocation of phosphorylated STAT1 in the nucleus. We found that LMWH binds with high affinity to IFNγ and is able to fully inhibit the interaction with its cellular receptor. It also influences the biological activity of IL-6 by binding to either IL-6 or IL-6/IL-6Rα, thus preventing the formation of the IL-6/IL-6Rα/gp130 signalling complex. These findings shed light on the molecular mechanism of the anti-inflammatory action of LMWH and underpin its ability to influence favourably conditions characterised by overexpression of these two cytokines. Such conditions are not only associated with autoimmune diseases, but also with inflammatory processes, in particular with COVID-19. Our results put forward heparin as a promising means for the prevention and suppression of severe CRS and encourage further investigations on its applicability as an anti-inflammatory agent.

摘要

我们的目标是揭示低分子量肝素 (LMWH) 的抗炎作用的分子机制，其基础是它对两种关键细胞因子 IFNγ 和 IL-6 活性的影响。通过广泛的分子动力学模拟研究了肝素与 IFNγ 和 IL-6 结合及其活性抑制的机制。通过测量其对刺激的 WISH 细胞中 IFNγ 信号转导的抗增殖活性和磷酸化 STAT1 在核内的易位，研究了 LMWH 对 IFNγ 信号转导的影响。我们发现 LMWH 与 IFNγ 具有高亲和力，能够完全抑制其与细胞受体的相互作用。它还通过与 IL-6 或 IL-6/IL-6Rα 结合来影响 IL-6 的生物学活性，从而阻止 IL-6/IL-6Rα/gp130 信号复合物的形成。这些发现阐明了 LMWH 抗炎作用的分子机制，并证明了它能够影响这两种细胞因子过表达的有利条件。这些条件不仅与自身免疫性疾病有关，还与炎症过程有关，特别是与 COVID-19 有关。我们的结果提出了肝素作为预防和抑制严重 CRS 的有前途的手段，并鼓励进一步研究其作为抗炎剂的适用性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03d4/8509397/1a2511663e7a/ijms-22-10730-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/03d4/8509397/1a2511663e7a/ijms-22-10730-g008.jpg
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