Multifactorial expression of IL-6 with update on COVID-19 and the therapeutic strategies of its blockade (Review)

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Abstract

Interleukin 6 (IL-6), a cytokine produced by various cells of the human body (macrophages, lymphocytes, astrocytes, ischemic myocytes, endothelial cells) has both pro-inflammatory and anti-inflammatory properties, being a key component in regulating various physiologic and pathological processes. The structure of this molecule and the receptor system it possesses are important due to the different activities that IL-6 can exert; through trans-signaling pro-inflammatory activities are mediated, while through classic signaling, IL-6 is responsible for anti-inflammatory and regenerative activities. IL-6 signaling is involved in coronary artery disease and the global COVID-19 pandemic. This proatherogenic cytokine reaches elevated serum levels in the cytokine storm generated by SARS-CoV-2, and is also associated with smoking or obesity-classic cardiovascular risk factors which promote inflammatory states. IL-6 levels are proportionally correlated with dyslipidemia, hypertension and glucose dysregulation, and they are associated with poor outcomes in patients with unstable angina or acute myocardial infarction. IL-6 targeting for treatment development (not only) in cardiovascular disease and COVID-19 is still a matter of ongoing research, although tocilizumab has proven to be effective in reducing the proatherogenic effects of IL-6 and is suggested to improve COVID-19 patient survival.

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The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

Chi Zhang, Zhao Wu, Jia-Wen Li … (2020)

Highlights • Pathogenesis of cytokine release syndrome in severe COVID-19 patients • The key role of IL-6 in cytokine release syndrome • Propose possible drugs IL-6R antagonist Tocilizumab for severe COVID-19

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Tocilizumab treatment in COVID‐19: A single center experience

Pan Luo, Yi. Liu, Lin Qiu … (2020)

Abstract Tocilizumab (TCZ), a monoclonal antibody against interleukin‐6 (IL‐6), emerged as an alternative treatment for COVID‐19 patients with a risk of cytokine storms recently. In the present study, we aimed to discuss the treatment response of TCZ therapy in COVID‐19 infected patients. The demographic, treatment, laboratory parameters of C‐reactive protein (CRP) and IL‐6 before and after TCZ therapy and clinical outcome in the 15 COVID‐19 patients were retrospectively assessed. Totally 15 patients with COVID‐19 were included in this study. Two of them were moderately ill, six were seriously ill and seven were critically ill. The TCZ was used in combination with methylprednisolone in eight patients. Five patients received the TCZ administration twice or more. Although TCZ treatment ameliorated the increased CRP in all patients rapidly, for the four critically ill patients who received an only single dose of TCZ, three of them (No. 1, 2, and 3) still dead and the CRP level in the rest one patient (No. 7) failed to return to normal range with a clinical outcome of disease aggravation. Serum IL‐6 level tended to further spiked firstly and then decreased after TCZ therapy in 10 patients. A persistent and dramatic increase of IL‐6 was observed in these four patients who failed treatment. TCZ appears to be an effective treatment option in COVID‐19 patients with a risk of cytokine storms. And for these critically ill patients with elevated IL‐6, the repeated dose of the TCZ is recommended.

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The inflammatory response in myocardial injury, repair, and remodelling.

Nikolaos G Frangogiannis (2014)

Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of postinfarction remodelling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited to the infarcted area, remove dead cells and matrix debris by phagocytosis, while preparing the area for scar formation. Timely repression of the inflammatory response is critical for effective healing, and is followed by activation of myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor β family are critically involved in suppression of inflammation and activation of a profibrotic programme. Translation of these concepts to the clinic requires an understanding of the pathophysiological complexity and heterogeneity of postinfarction remodelling in patients with myocardial infarction. Individuals with an overactive and prolonged postinfarction inflammatory response might exhibit left ventricular dilatation and systolic dysfunction and might benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with an exaggerated fibrogenic reaction can develop heart failure with preserved ejection fraction and might require inhibition of the Smad3 (mothers against decapentaplegic homolog 3) cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies.

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Author and article information

Journal

Journal ID (nlm-ta): Exp Ther Med

Journal ID (iso-abbrev): Exp Ther Med

Journal ID (publisher-id): ETM

Title: Experimental and Therapeutic Medicine

Publisher: D.A. Spandidos

ISSN (Print): 1792-0981

ISSN (Electronic): 1792-1015

Publication date (Print): March 2021

Publication date (Electronic): 25 January 2021

Publication date PMC-release: 25 January 2021

Volume: 21

Issue: 3

Electronic Location Identifier: 263

Affiliations

[1 ]Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800010 Galati, Romania

[2 ]Cardio-Thoracic Department, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania

[3 ]Clinical Cardiology Department, ‘Bagdasar Arseni’ Emergency Hospital, 041915 Bucharest, Romania

[4 ]Department of Pharmaceutical Sciences, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800010 Galati, Romania

[5 ]Research Center in The Field of Medical and Pharmaceutical Sciences, ReFORM-UDJ, ‘Dunărea de Jos’ University, 800010 Galati, Romania

[6 ]Department of Diabetic Foot Care, ‘Prof. N. Paulescu’ National Institute of Diabetes, 011233 Bucharest, Romania

[7 ]Clinical Department, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800010 Galati, Romania

[8 ]Department of Dermatology, ‘Sf. Cuvioasa Parascheva’ Clinical Hospital of Infectious Diseases, 800179 Galati, Romania

[9 ]Centre of Medical-Pharmaceutical Research, ‘Dunărea de Jos’ University, 800010 Galati, Romania

[10 ]Department of Dermato-Venereology, Doctoral School, University of Medicine and Pharmacy ‘Gr. T. Popa’, 700115 Iași, Romania

[11 ]Department of Pediatrics, ‘Sf. Ioan’ Clinical Hospital for Children, 800487 Galati, Romania

Author notes

Correspondence to: Dr Mihaela Craescu, Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 35 Al. I. Cuza Street, 800010 Galati, Romania dr.craescumihaela@ 123456yahoo.ro

Dr Diana Sabina Radaschin, Research Center in The Field of Medical and Pharmaceutical Sciences, ReFORM-UDJ, ‘Dunărea de Jos’ University, 35 Al. I. Cuza Street, 800010 Galati, Romania dianaradaschin@ 123456yahoo.com

^*Contributed equally

Article

Publisher ID: ETM-0-0-09693

DOI: 10.3892/etm.2021.9693

PMC ID: 7851683

PubMed ID: 33603870

SO-VID: 091d4811-90d6-4444-9902-74094f2e18f0

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This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Multifactorial expression of IL-6 with update on COVID-19 and the therapeutic strategies of its blockade (Review)

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Novel Coronavirus Disease COVID-19

Most cited references 111

The cytokine release syndrome (CRS) of severe COVID-19 and Interleukin-6 receptor (IL-6R) antagonist Tocilizumab may be the key to reduce the mortality

Tocilizumab treatment in COVID‐19: A single center experience

The inflammatory response in myocardial injury, repair, and remodelling.

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