Molecular Mechanism of the Anti-Inflammatory Action of Heparin

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...

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Bibliographic Details
Published in:International journal of molecular sciences 2021-10, Vol.22 (19), p.10730
Main Authors: Litov, Leandar, Petkov, Peicho, Rangelov, Miroslav, Ilieva, Nevena, Lilkova, Elena, Todorova, Nadezhda, Krachmarova, Elena, Malinova, Kristina, Gospodinov, Anastas, Hristova, Rossitsa, Ivanov, Ivan, Nacheva, Genoveva
Format: Article
Language:English
Subjects:
Anti-inflammatory agents
Anticoagulants
Autoimmune diseases
Binding
Binding sites
Biological activity
Carbohydrates
Coronaviruses
COVID-19
Cytokine storm
Glycoprotein gp130
Heparan sulfate
Heparin
Hydrogen bonds
IFNγ
Inflammation
Interleukin 6
low-molecular-weight heparin (LMWH)
Molecular dynamics
molecular modelling
Proteins
Simulation
Solvents
Stat1 protein
γ-Interferon
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Summary: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.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms221910730