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World J Virol. May 25, 2022; 11(3): 113-128
Published online May 25, 2022. doi: 10.5501/wjv.v11.i3.113
Severe acute respiratory syndrome coronavirus 2 infection: Role of interleukin-6 and the inflammatory cascade
Mohaddeseh Bahmani, Rojin Chegini, Elham Ghanbari, Elham Sheykhsaran, Parisa Shiri Aghbash, Hamed Ebrahimzadeh Leylabadlo, Ehsan Moradian, Amir Masoud Kazemzadeh Houjaghan, Hossein Bannazadeh Baghi
Mohaddeseh Bahmani, Department of Virology, Student Research Committee, Tabriz Univer-sity of Medical Sciences, Tabriz 15731, Iran
Rojin Chegini, Department of Medical Science, Metabolic Liver Disease Research Center, Isfahan University of Medical Sciences, Isfahan 81745-33871, Iran
Elham Ghanbari, Department of Medical Science, Fertility and Infertility Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 67159-59167, Iran
Elham Sheykhsaran, Department of Microbiology, Student Research Committee, Tabriz University of Medical Sciences, Tabriz 15731, Iran
Elham Sheykhsaran, Parisa Shiri Aghbash, Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 15731, Iran
Parisa Shiri Aghbash, Department of Virology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz 15731, Iran
Hamed Ebrahimzadeh Leylabadlo, Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz 15731, Iran
Ehsan Moradian, Department of Medical Science, Medical Faculty, Tabriz University of Medical Sciences, Tabriz 5165665931, Iran
Amir Masoud Kazemzadeh Houjaghan, Department of Internal Medicine, Medical Faculty, Tehran University of Medical Sciences, Tehran 14155-6559, Iran
Hossein Bannazadeh Baghi, Department of Virology, Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz 15731, Iran
Author contributions: Bahmani M, Bannazadeh Baghi H, and Chegini R contributed to the conceptualization; Bahmani M, Chegini R, and Ghanbari E contributed to writing - original draft; Shiri Aghbash P, and Bannazadeh Baghi H contributed to writing - review and editing; Shiri Aghbash P, Bannazadeh Baghi H, Chegini R, and Sheykhsaran E contributed to the visualization; Leylabadlo HE, Bannazadeh Baghi H, Shiri Aghbash P, Ghanbari E, and Sheykhsaran E contributed to the supervision; Bannazadeh Baghi H and Shiri Aghbash P contributed to the project administration; Moradian E, and Kazemzadeh Houjaghan AM contributed to the language editing.
Conflict-of-interest statement: The authors declare that there are no conflicts of interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hossein Bannazadeh Baghi, PhD, Associate Professor, Department of Virology, Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz 15731, Iran. hbannazadeh@tbzmed.ac.ir
Received: December 14, 2021
Peer-review started: December 14, 2021
First decision: February 15, 2022
Revised: March 3, 2022
Accepted: April 28, 2022
Article in press: April 28, 2022
Published online: May 25, 2022
Processing time: 156 Days and 17.1 Hours
Abstract

Since December 2019, a novel coronavirus that represents a serious threat to human lives has emerged. There is still no definite treatment for severe cases of the disease caused by this virus, named coronavirus disease 2019 (COVID-19). One of the most considered treatment strategies targets the exaggerated immune regulator, and interleukin (IL)-6 is a crucial pro-inflammatory mediator. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cases show an elevated level of IL-6 related to disease severity. IL-6 activity can be inhibited by the following: IL-6 itself, IL-6 signaling pathways such as Janus kinase and signal transducer and activator of transcription (JAK-STAT), gp130, IL-6R, and downstream activated ILs, such as IL-17 and IL-6 cytokine. Currently, according to these studies and their results, IL-6 blockade with anti-IL-6 or its receptor antibodies such as tocilizumab in COVID-19 is beneficial in severe cases and may reduce the mortality rate. JAK-STAT inhibitors block the cytokine storm by inhibiting several crucial pro-inflammatory mediators such as TNF-α and IL-6 and have shown various results in clinical trials. IL-6 induces IL-17 secretion, and IL-17 is involved in the pathogenesis of inflammatory processes. Clinical trials of anti-IL-17 drugs are currently recruiting, and anti-gp130 antibody is preclinical. However, this agent has shown positive effects in inflammatory bowel disease clinical trials and could be tested for SARS-CoV-2. This study aimed to review the role of IL-6 in the cytokine storm and studies regarding IL-6 and blockade of its inflammatory pathways in COVID-19 to determine if any of these agents are beneficial for COVID-19 patients.

Keywords: Anti-interleukin-6, COVID-19, Inflammation, Interleukin-6, Interleukin-6 receptor, SARS-CoV-2

Core Tip: One of the most considered treatment strategies for severe acute respiratory syndrome coronavirus 2 is targeting the immune response and pro-inflammatory cytokines such as interleukin (IL)-6. Patients with severe acute respiratory syndrome coronavirus 2 show elevated levels of IL-6, which is related to disease severity. Current studies have shown that IL-6 blockade by anti-IL-6 or its receptor antibodies such as tocilizumab is beneficial in severe cases and may reduce the mortality rate. Moreover, the combination of anti-inflammatory agents is more effective than single therapy.