Current Science

Open Access Open Access  Restricted Access Subscription Access

Interleukin-6, a major player of cytokine storm in COVID-19 and its alleviation by therapeutic antibodies


Affiliations
1 Centre for BioSeparation Technology, Vellore Institute of Technology, Vellore 632 014, India
 

Interleukin-6 (IL-6) is an important cytokine that plays a vital role in immune response and inflamma-tion. Here, the signalling functions of IL-6 through its receptors, physiological and pathological roles, espe-cially its contribution to various autoimmune diseases, cancers and severe COVID-19/SARS-CoV2 infections are described. It is reported that in severe COVID-19 infection and auto-immune diseases, the patients expe-rience cytokine storms due to hyper-activation of the IL-6 receptor pathway leading to detrimental effects. Blocking IL-6 receptor action by therapeutic antibodies has been considered an attractive strategy of treat-ment. The latest findings on the application of anti-IL-6 therapeutic antibodies in COVID-19 patients are also discussed.



Keywords

COVID-19 infection, cytokine storm, im-mune response, interleukin-6, therapeutic antibodies.
User
Notifications
Font Size

  • Kumar, P. and Mina, U., Life Sciences: Fundamentals and Practice-1 (Fifth Edition), Pathfinder Publication, New Delhi, 2015, pp. 459–534.

  • World Health Organization, WHO coronavirus (COVID-19) dash-board with vaccination data; https://covid19.who.int/ (accessed on 10 June 2022).

  • Tang, Y. et al., Cytokine storm in COVID-19: the current evidence and treatment strategies. Front. Immunol., 2020, 11, 1708.

  • Atal, S. and Fatima, Z., IL-6 inhibitors in the treatment of serious COVID-19: a promising therapy? Pharma. Med., 2020, 34, 223– 231.

  • Fajgenbaum, D. C. and June, C. H., Cytokine storm. N. Engl. J. Med., 2020, 383, 2255–2273.

  • Chen, L. Y. C., Hoiland, R. L., Stukas, S., Wellington, C. L. and Sekhon, M. S., Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome. Eur. Respir. J., 2020, 56, 2003006.

  • Velazquez-Salinas, L., Verdugo-Rodriguez, A., Rodriguez, L. L. and Borca, M. V., The role of interleukin-6 during viral infections. Front. Microbiol., 2019, 10, 1057.

  • Wojdasiewicz, P., Poniatowski, A. A. and Szukiewicz, D., The role of inflammatory and anti-inflammatory cytokines in the patho-genesis of osteoarthritis. Med. Inflamm., 2014, 2014, 561459; doi: 10.1155/2014/561459.

  • Chalaris, A., Garbers, C., Rabe, B., Rose-John, S. and Scheller, J., The soluble interleukin-6 receptor: generation and role in inflam-mation and cancer. Eur. J. Cell Biol., 2011, 90, 484–494.

  • Brocke-Heidrich, K. et al., Interleukin-6-dependent gene expres-sion profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family-independent survival pathway closely associated with Stat3 activation. Blood, 2004, 103, 242–251.

  • Wongchana, W. and Palaga, T., Direct regulation of interleukin-6 expression by Notch signaling in macrophages. Cell. Mol. Immu-nol., 2012, 9, 155–162.

  • Jones, S. A. and Jenkins, B. J., Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nature Rev. Immunol., 2018, 18, 773–789.

  • Kang, S., Narazaki, M., Metwally, H. and Kishimoto, T., Historical overview of the interleukin-6 family cytokine. J. Exp. Med., 2020, 217, 20190347.

  • Murakami, M. and Hirano, T., The pathological and physiological roles of IL-6 amplifier activation. Int. J. Biol. Sci., 2012, 8, 1267–1280.

  • Ohsugi, Y., The immunobiology of humanized Anti-IL6 receptor antibody: from basic research to breakthrough medicine. J. Transl. Autoimmun., 2020, 3, 100030.

  • Mihara, M., Hashizume, M., Yoshida, H., Suzuki, M. and Shiina, M., IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin. Sci., 2012, 122, 143–159.

  • Castell, J. V. et al., Interleukin-6 is the major regulator of acute phase protein synthesis in adult human hepatocytes. FEBS Lett., 1989, 242, 237–239.

  • Ebrabem, Q., Minamoto, A., Hoppe, G., Anand-Apte, B. and Sears, J. E., Triamcinolone acetonide inhibits IL-6- and VEGF-induced angiogenesis downstream of the IL-6 and VEGF receptors. Invest. Ophthalmol. Vis. Sci., 2006, 47, 4935–4941.

  • Fielding, C. A. et al., IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J. Immunol., 2008, 181, 2189–2195.

  • Tanaka, T., Narazaki, M. and Kishimoto, T., IL-6 in inflammation, immunity, and disease. Cold Spring Harbour Perspect. Biol., 2014, 6, 1–16.

  • Väänänen, H. K. and Härkönen, P. L., Estrogen and bone meta-bolism. Maturitas, 1996, 23, S65–S69.

  • Poli, V. et al., Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J., 1994, 13, 1189–1196.

  • Nakajima, S. et al., Interleukin-6 inhibits early differentiation of ATDC5 chondrogenic progenitor cells. Cytokine, 2009, 47, 91–97.

  • Tsuchida, A. I. et al., Interleukin-6 is elevated in synovial fluid of patients with focal cartilage defects and stimulates cartilage matrix production in an in vitro regeneration model. Arthritis Res. Ther., 2012, 14, R262.

  • Feldmann, M., Brennan, F. M. and Maini, R. N., Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol., 1996, 14, 397–440.

  • Kishimoto, T., Kang, S. and Tanaka, T., IL-6: a new era for the treatment of autoimmune inflammatory diseases. In Innovative Medicine, Springer, Japan, 2015, pp. 131–147; doi:10.1007/978-4-431-55651-0_11.

  • Dougados, M. et al., Adding tocilizumab or switching to tocili-zumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann. Rheum. Dis., 2013, 72, 43–50.

  • Sandborg, C. and Mellins, E. D., A new era in the treatment of systemic juvenile idiopathic arthritis. N. Engl. J. Med., 2012, 367, 2439–2440.

  • Tackey, E., Lipsky, P. E. and Illei, G. G., Rationale for interleukin-6 blockade in systemic lupus erythematosus. Lupus, 2004, 13, 339–343.

  • Krei, K., Fredrikson, S., Fontana, A. and Link, H., Interleukin-6 is elevated in plasma in multiple sclerosis. J. Neuroimmunol., 1991, 31, 147–153.

  • Ashtari, F., Madanian, R., Shaygannejad, V., Zarkesh, S. H. and Ghadimi, K., Serum levels of IL-6 and IL-17 in multiple sclerosis, neuromyelitis optica patients and healthy subjects. Int. J. Physiol. Pathophysiol. Pharmacol., 2019, 11, 267.

  • Masjedi, A. et al., The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed. Pharmacother., 2018, 108, 1415–1424.

  • Bromberg, J. and Wang, T. C., Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell, 2009, 15, 79–80.

  • Yang, X. et al., Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir. Med., 2020, 8, 475–481.

  • Abbasifard, M. and Khorramdelazad, H., The bio-mission of inter-leukin-6 in the pathogenesis of COVID-19: a brief look at potential therapeutic tactics. Life Sci., 2020, 257, 118097.

  • Huang, C. et al., Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 2020, 395, 497–506.

  • Conti, P. et al., Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by coronavirus-19 (COVID-19 or SARS-CoV-2): anti-inflammatory strategies. J. Biol. Regul. Homeost. Agents, 2020, 34, 327–331.

  • Martinez, N. E. et al., Regulatory T cells and Th17 cells in viral infections: implications for multiple sclerosis and myocarditis. Future Virol., 2012, 7, 593–608.

  • Lauder, S. N. et al., Interleukin-6 limits influenza-induced inflam-mation and protects against fatal lung pathology. Eur. J. Immunol., 2013, 43, 2613–2625.

  • Hashizume, M., Outlook of IL-6 signaling blockade for COVID-19 pneumonia. Inflamm. Regen., 2020, 40, 24.

  • Scherger, S., Henao-Martínez, A., Franco-Paredes, C. and Shapiro, L., Rethinking interleukin-6 blockade for treatment of COVID-19. Med. Hypotheses, 2020, 144, 110053.

  • US National Library of Medicine, Anti-IL6 treatment of serious COVID-19 disease with threatening respiratory failure, sponsored by Henriksen, M., 2020; https://www.clinicaltrials.gov/ct2/show/NCT- 04322773

  • Luo, P. et al., Tocilizumab treatment in COVID-19: a single center experience. J. Med. Virol., 2020, 92, 814–818.

  • Samaee, H., Mohsenzadegan, M., Ala, S., Maroufi, S. S. and Mora-dimajd, P., Tocilizumab for treatment patients with COVID-19: recommended medication for novel disease. Int. Immunopharmacol., 2020, 89, 107018.

  • Stone, J. H. et al., Efficacy of tocilizumab in patients hospitalized with COVID-19. N. Engl. J. Med., 2020, 383, 2333–2344.

  • Salama, C. et al., Tocilizumab in patients hospitalized with COVID-19 pneumonia. N. Engl. J. Med., 2021, 384, 20–30.

  • Lomakin, N. V. et al., The efficacy and safety of levilimab in severely ill COVID-19 patients not requiring mechanical ventilation: results of a multicenter randomized double-blind placebo-controlled phase III CORONA clinical study. Inflamm. Res., 2021, 70(10–12), 1233–1246.

  • Reichert, J., Anti-IL-6R levilimab registered as COVID-19 treatment in Russia – The Antibody Society, 2020; https://www.antibody-society.org/approvals/anti-il-6r-levilimab-registered-as-covid-19-treat-ment-in-russia/

  • Basu, M., Russia approves levilimab for treating severe Covid-19 patients, says it reduces death risk, 2020; https://theprint.in/ health/russia-approves-levilimab-for-treating-severe-covid-19-pati-ents-says-it-reduces-death-risk/439094/

  • Shaw, S. et al., Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling. MAbs, 2014, 6, 773.

  • Antonov, V. N. et al., Experience of olokizumab use in COVID-19 patients. Тherapeutic Archive, 2020, 92, 148–154.

  • Della-Torre, E. et al., Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: an open-label cohort study. Ann. Rheum. Dis., 2020, 79, 1277–1285.

  • Genovese, M. C. et al., Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheumatol., 2015, 67, 1424–1437.

  • US National Library of Medicine, A study to evaluate the efficacy and safety of sirukumab in confirmed severe or critical confirmed coronavirus disease (COVID-19), sponsored by Janssen Biophar-maceuticals, 2021; https://www.clinicaltrials.gov/ct2/show/study/ NCT04380961

  • Luo, P. et al., Tocilizumab treatment in COVID-19: a single center experience. J. Med. Virol., 2020, 92(7), 814–818.

  • US National Library of Medicine, Study of the efficacy and safety of a single administration of olokizumab and RPH-104 with standard therapy in patients with severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2) infection (COVID-19), sponsored by R-Pharma International, LLC, 2022; https://clinicaltrials.gov/ct2/show/ NCT04380519

  • US National Library of Medicine, Sarilumab COVID-19, sponsored by Sanofi, 2021; https://clinicaltrials.gov/ct2/show/NCT04327388


Abstract Views: 307

PDF Views: 139




  • Interleukin-6, a major player of cytokine storm in COVID-19 and its alleviation by therapeutic antibodies

Abstract Views: 307  |  PDF Views: 139

Authors

Kumar Simant
Centre for BioSeparation Technology, Vellore Institute of Technology, Vellore 632 014, India
Krishnan Venkataraman
Centre for BioSeparation Technology, Vellore Institute of Technology, Vellore 632 014, India

Abstract


Interleukin-6 (IL-6) is an important cytokine that plays a vital role in immune response and inflamma-tion. Here, the signalling functions of IL-6 through its receptors, physiological and pathological roles, espe-cially its contribution to various autoimmune diseases, cancers and severe COVID-19/SARS-CoV2 infections are described. It is reported that in severe COVID-19 infection and auto-immune diseases, the patients expe-rience cytokine storms due to hyper-activation of the IL-6 receptor pathway leading to detrimental effects. Blocking IL-6 receptor action by therapeutic antibodies has been considered an attractive strategy of treat-ment. The latest findings on the application of anti-IL-6 therapeutic antibodies in COVID-19 patients are also discussed.



Keywords


COVID-19 infection, cytokine storm, im-mune response, interleukin-6, therapeutic antibodies.

References





DOI: https://doi.org/10.18520/cs%2Fv123%2Fi6%2F745-753