296
Views
4
Downloads
0
Crossref
N/A
WoS
0
Scopus
0
CSCD
Interleukin 6 (IL-6) is a cytokine with dual functions of pro-inflammation and anti-inflammation. It is mainly produced by mononuclear macrophages, Th2 cells, vascular endothelial cells and fibroblasts. IL-6 binds to glycoprotein 130 and one of these two receptors, membrane-bound IL-6R or soluble IL-6R, forming hexamer (IL-6/IL-6R/gp130), which then activates different signaling pathways (classical pathway, trans-signaling pathway) to exert dual immune-modulatory effects of anti-inflammation or pro-inflammation. Abnormal levels of IL-6 can cause multiple pathological reactions, including cytokine storm. Related clinical studies have found that IL-6 levels in severe COVID-19 patients were much higher than in healthy population. A large number of studies have shown that IL-6 can trigger a downstream cytokine storm in patients with COVID-19, resulting in lung damages, aggravating clinical symptoms and developing excessive inflammation and acute respiratory distress syndrome (ARDS). Monoclonal antibodies against IL-6 or IL-6R, such as tocilizumab, sarilumab, siltuximab and olokizumab may serve as therapeutic options for COVID-19 infection.
Interleukin 6 (IL-6) is a cytokine with dual functions of pro-inflammation and anti-inflammation. It is mainly produced by mononuclear macrophages, Th2 cells, vascular endothelial cells and fibroblasts. IL-6 binds to glycoprotein 130 and one of these two receptors, membrane-bound IL-6R or soluble IL-6R, forming hexamer (IL-6/IL-6R/gp130), which then activates different signaling pathways (classical pathway, trans-signaling pathway) to exert dual immune-modulatory effects of anti-inflammation or pro-inflammation. Abnormal levels of IL-6 can cause multiple pathological reactions, including cytokine storm. Related clinical studies have found that IL-6 levels in severe COVID-19 patients were much higher than in healthy population. A large number of studies have shown that IL-6 can trigger a downstream cytokine storm in patients with COVID-19, resulting in lung damages, aggravating clinical symptoms and developing excessive inflammation and acute respiratory distress syndrome (ARDS). Monoclonal antibodies against IL-6 or IL-6R, such as tocilizumab, sarilumab, siltuximab and olokizumab may serve as therapeutic options for COVID-19 infection.
Aeschlimann FA, Dumaine C, Wörner A, Mouy R, Wouters C, Melki I, Uettwiller F, Job-Deslandre C, Quartier P, Bader-Meunier B (2020) Serious adverse events in children with juvenile idiopathic arthritis and other rheumatic diseases on tocilizumab – a real-world experience. Semin Arthritis Rheum 50(4): 744−748
Alende-Castro V, Alonso-Sampedro M, Gude F, Gonzalez-Quintela A (2020) Serum concentrations of interleukin-6 (IL-6) in the general adult population: possible implications for anti-IL-6 therapy in SARS-Cov-2 infection and IL-6-related diseases. J Investig Allergol Clin Immunol 31(1): 75−78
Alzghari SK, Acuna VS (2020) Supportive treatment with tocilizumab for COVID-19: a systematic review. J Clin Virol 127: 104380. https://doi.org/10.1016/j.jcv.2020.104380
Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, Al-Rabiah FA, Al-Hajjar S, Al-Barrak A, Flemban H, Al-Nassir WN, Balkhy HH, Al-Hakeem RF, Makhdoom HQ, Zumla AI, Memish ZA (2013) Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study. Lancet Infect Dis 13(9): 752−761
Atzeni F, Nucera V, Masala IF, Sarzi-Puttini P, Bonitta G (2019) Il-6 Involvement in pain, fatigue and mood disorders in rheumatoid arthritis and the effects of Il-6 inhibitor sarilumab. Pharmacol Res 149: 104402. https://doi.org/10.1016/j.phrs.2019.104402
Benucci M, Giannasi G, Cecchini P, Gobbi FL, Damiani A, Grossi V, Infantino M, Manfredi M (2020) COVID-19 pneumonia treated with sarilumab: a clinical series of eight patients. J Med Virol 92(11): 2368−2370
Berlin DA, Gulick RM, Martinez FJ (2020) Severe Covid-19. N Engl J Med 383(25): 2451−2460
Boyce EG, Rogan EL, Vyas D, Prasad N, Mai Y (2018) sarilumab: review of a second IL-6 receptor antagonist indicated for the treatment of rheumatoid arthritis. Ann Pharmacother 52(8): 780−791
Campochiaro C, Della-Torre E, Cavalli G, De Luca G, Ripa M, Boffini N, Tomelleri A, Baldissera E, Rovere-Querini P, Ruggeri A, Monti G, De Cobelli F, Zangrillo A, Tresoldi M, Castagna A, Dagna L (2020) Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study. Eur J Int Med 76: 43−49
Chen F, Teachey DT, Pequignot E, Frey N, Porter D, Maude SL, Grupp SA, June CH, Melenhorst JJ, Lacey SF (2016) Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J Immunol Methods 434: 1−8
Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, Zhang X, Zhang M, Wu S, Song J, Chen T, Han M, Li S, Luo X, Zhao J, Ning Q (2020a) Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 130(5): 2620−2629
Chen J, Lau YF, Lamirande EW, Paddock CD, Bartlett JH, Zaki SR, Subbarao K (2010) Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J Virol 84(3): 1289−1301
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia Ja, Yu T, Zhang X, Zhang L (2020b) Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet 395(10223): 507−513
Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y, Men D, Huang Q, Liu Y, Yang B, Ding J, Li F (2020c) Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely associated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin Infect Dis 71(8): 1937−1942
Chomarat P, Banchereau J, Davoust J, Palucka AKJNI (2000) IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol 1(6): 510−514
Chuan Q, Luoqi Z, Ziwei H, Shuoqi Z, Sheng Y, Yu T, Cuihong X, Ke M, Ke S, Wei W, Dai-Shi T (2020) Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis 71(15): 762−768
Cifaldi L, Prencipe G, Caiello I, Bracaglia C, Locatelli F, De Benedetti F, Strippoli R (2015) Inhibition of natural killer cell cytotoxicity by interleukin-6: implications for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol 67(11): 3037−3046
Cipriani A, Zorzi A, Ceccato D, Capone F, Parolin M, Donato F, Fioretto P, Pesavento R, Previato L, Maffei P, Saller A, Avogaro A, Sarais C, Gregori D, Iliceto S, Vettor R (2020) Arrhythmic profile and 24-hour QT interval variability in COVID-19 patients treated with hydroxychloroquine and azithromycin. Int J Cardiol 316: 280−284
Coomes EA, Haghbayan H (2020) Interleukin-6 in COVID-19: a systematic review and meta-analysis. Rev Med Virol 30(6): 1−9
Corominas H, Castellvi I, Domingo P, Casademont J (2020) Facing the SARS-CoV-2 (COVID-19) outbreak with IL-6R antagonists. Eur J Rheumatol 7(Suppl 2): S107−S109
Cunningham L, Kimber I, Basketter DA, McFadden JP (2020) Why judiciously timed anti-IL 6 therapy may be of benefit in severe COVID-19 infection. Autoimmun Rev 19(7): 102563. https://doi.org/10.1016/j.autrev.2020.102563
Dai L, Zheng T, Xu K, Han Y, Xu L, Huang E, An Y, Cheng Y, Li S, Liu M, Yang M, Li Y, Cheng H, Yuan Y, Zhang W, Ke C, Wong G, Qi J, Qin C, Yan J, Gao GF (2020) A universal design of betacoronavirus vaccines against COVID-19, MERS and SARS. Cell 182(3): 722−733
Dhall A, Patiyal S, Sharma N, Usmani SS, Raghava GPS (2020) Computer-aided prediction and design of IL-6 inducing peptides: IL-6 plays a crucial role in COVID-19. Brief Bioinform 22(2): 936−945
Diehl S, Rincón M (2002) The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol 39(9): 531−536
Düsterhöft S, Lokau J, Garbers C (2019) The metalloprotease ADAM17 in inflammation and cancer. Pathol Res Pract 215(6): 152410. https://doi.org/10.1016/j.prp.2019.04.002
Elias JA, Lentz V (1990) IL-1 and tumor necrosis factor synergistically stimulate fibroblast IL-6 production and stabilize IL-6 messenger RNA. J Immunol 145(1): 161−166
Fajgenbaum DC, Kurzrock RJI (2016) Siltuximab: a targeted therapy for idiopathic multicentric Castleman disease. Immunotherapy 8(1): 17−26
Fang Y, Zhang H, Xu Y, Xie J, Pang P, Ji W (2020) CT manifestations of two cases of 2019 novel coronavirus (2019-nCoV) pneumonia. Radiology 295(1): 208−209
Foldvari-Nagy L, Schnabel T, Dornyei G, Korcsmaros T, Lenti K (2021) On the role of bacterial metalloproteases in COVID-19 associated cytokine storm. Cell Commun Signal 19(1): 7. https://doi.org/10.1186/s12964-020-00699-3
Gabriels J, Saleh M, Chang D, Epstein LM (2020) Inpatient use of mobile continuous telemetry for COVID-19 patients treated with hydroxychloroquine and azithromycin. HeartRhythm Case Rep 6(5): 241−243
Gao Y, Li T, Han M, Li X, Wu D, Xu Y, Zhu Y, Liu Y, Wang X, Wang L (2020) Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19. J Med Virol 92(7): 791−796
Gao YM, Xu G, Wang B, Liu BC (2021) Cytokine storm syndrome in coronavirus disease, 2019: a narrative review. J Intern Med 289(2): 147−161
Garbers C, Jänner N, Chalaris A, Moss ML, Floss DM, Meyer D, Koch-Nolte F, Rose-John S, Scheller J (2011) Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding. J Biol Chem 286(17): 14804−14811
Genovese MC, Fleischmann R, Furst D, Janssen N, Carter J, Dasgupta B, Bryson J, Duncan B, Zhu W, Pitzalis C, Durez P, Kretsos K (2014) Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis 73(9): 1607−1615
Goursaud S, Descamps R, Daubin C, du Cheyron D, Valette X (2020) Corticosteroid use in selected patients with severe acute respiratory distress syndrome related to COVID-19. J Infect 81(2): e89−e90
Gubernatorova EO, Gorshkova EA, Polinova AI, Drutskaya MD (2020) IL-6: relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev 53: 13−24
Guo W, Li M, Dong Y, Zhou H, Research DHJDM, Reviews (2020) Diabetes is a risk factor for the progression and prognosis of COVID-19. Diabetes Metab Res Rev 36(7): e3319. https://doi.org/10.1002/dmrr.3319
Hasan SS, Capstick T, Zaidi STR, Kow CS, Merchant HA (2020) Use of corticosteroids in asthma and COPD patients with or without COVID-19. Respir Med 170: 106045. https://doi.org/10.1016/j.rmed.2020.106045
Hashizume M (2020) Outlook of IL-6 signaling blockade for COVID-19 pneumonia. Inflamm Regen 40(1): 24. https://doi.org/10.1186/s41232-020-00134-7
He Z, Zhao C, Dong Q, Zhuang H, Song S, Peng G, Dwyer DE (2005) Effects of severe acute respiratory syndrome (SARS) coronavirus infection on peripheral blood lymphocytes and their subsets. Int J Infect Dis 9(6): 323−330
Herold T, Jurinovic V, Arnreich C, Lipworth BJ, Hellmuth JC, Bergwelt-Baildon Mv, Klein M, Weinberger T (2020b) Elevated levels of interleukin-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol 146(1): 128−136
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395(10223): 497−506
Ilmarinen P, Tuomisto LE, Niemelä O, Danielsson J, Haanpää J, Kankaanranta T, Kankaanranta H (2016) Comorbidities and elevated IL-6 associate with negative outcome in adult-onset asthma. Eur Respir J 48(4): 1052−1062
Jones G, Sebba A, Gu J, Lowenstein MB, Genovese MCJAotRD (2010) Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 69(1): 88−96
Jones SA, Jenkins BJ (2018) Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol 18(12): 773−789
Kaplon H, Reichert JM (2021) Antibodies to watch in 2021. MAbs 13(1): 1860476. https://doi.org/10.1080/19420862.2020.1860476
Kaur S, Bansal Y, Kumar R, Bansal G (2020) A panoramic review of IL-6: structure, pathophysiological roles and inhibitors. Bioorg Med Chem 28(5): 115327. https://doi.org/10.1016/j.bmc.2020.115327
Kelleni MT (2020) Nitazoxanide/azithromycin combination for COVID-19: a suggested new protocol for early management. Pharmacol Res 157: 104874. https://doi.org/10.1016/j.phrs.2020.104874
Kewan T, Covut F, Al–Jaghbeer MJ, Rose L, Gopalakrishna KV, Akbik B (2020) Tocilizumab for treatment of patients with severe COVID–19: a retrospective cohort study. EClinicalMedicine 24: 100418. https://doi.org/10.1016/j.eclinm.2020.100418
Klopfenstein T, Zayet S, Lohse A, Balblanc JC, Badie J, Royer PY, Toko L, Mezher C, Kadiane-Oussou NJ, Bossert M, Bozgan AM, Charpentier A, Roux MF, Contreras R, Mazurier I, Dussert P, Gendrin V, Conrozier T (2020) Tocilizumab therapy reduced intensive care unit admissions and/or mortality in COVID-19 patients. Med Mal Infect 50(5): 397−400
Kurokouchi K, Kambe F, Yasukawa K, Izumi R, Ishiguro N, Iwata H, Seo H (1998) TNF-alpha increases expression of IL-6 and ICAM-1 genes through activation of NF-kappaB in osteoblast-like ROS17/2.8 cells. J Bone Miner Res 13(8): 1290−1299
Lavillegrand J-R, Garnier M, Spaeth A, Mario N, Hariri G, Pilon A, Berti E, Fieux F, Thietart S, Urbina T, Turpin M, Darriviere L, Fartoukh M, Verdonk F, Dumas G, Tedgui A, Guidet B, Maury E, Chantran Y, Voiriot G, Ait-Oufella H (2021) Elevated plasma IL-6 and CRP levels are associated with adverse clinical outcomes and death in critically ill SARS-CoV-2 patients: inflammatory response of SARS-CoV-2 patients. Ann Intensive Care 11(1): 9. https://doi.org/10.1186/s13613-020-00798-x
Le RQ, Li L, Yuan W, Shord SS, Nie L, Habtemariam BA, Farrell AT, Przepiorka D (2018) Tocilizumab for treatment of severe or life-threatening chimeric antigen receptor T cell-induced cytokine release syndrome—FDA approval summary. Biol Blood Marrow Transplant 24(3, Supplement): S172. https://doi.org/10.1016/j.bbmt.2017.12.104
Li G, He X, Zhang L, Ran Q, Wang J, Xiong A, Wu D, Chen F, Sun J, Chang C (2020a) Assessing ACE2 expression patterns in lung tissues in the pathogenesis of COVID-19. J Autoimmun 112: 102463. https://doi.org/10.1016/j.jaut.2020.102463
Li H, Ma N (2020) Feasibility of COVID-19 severe patients with ulinastatin. Chin Trad Herbal Drugs 43(5): 959−963
Li X, Xu Y, Wang L, Yang Z, Li Y, Dawei T, Zhihai C, Rui S (2020b) Clinical research of glucocorticoid treatment in severe cases of COVID-19. J Cap Med Univ 19: 345−349
Lipworth B, Chan R, Lipworth S, Kuo CR (2020) Weathering the cytokine storm in susceptible patients with severe SARS-CoV-2 infection. J Allergy Clin Immunol Pract 8(6): 1798−1801
Liu B, Li M, Zhou Z, Guan X, Xiang Y (2020) Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun 111: 102452. https://doi.org/10.1016/j.jaut.2020.102452
Lust JA, Donovan KA, Kline MP, Greipp PR, Kyle RA, Maihle NJ (1992) Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine 4(2): 96−100
Magro G (2020) SARS-CoV-2 and COVID-19: is interleukin-6 (IL-6) the 'culprit lesion' of ARDS onset? What is there besides tocilizumab? SGP130Fc. Cytokine X 2(2): 100029. https://doi.org/10.1016/j.cytox.2020.100029
Mahmudpour M, Roozbeh J, Keshavarz M, Farrokhi S, Nabipour I (2020) COVID-19 cytokine storm: the anger of inflammation. Cytokine 133: 155151. https://doi.org/10.1016/j.cyto.2020.155151
McElvaney OJ, McEvoy NL, McElvaney OF, Carroll TP, Murphy MP, Dunlea DM, O NC, Clarke J, O'Connor E, Hogan G, Ryan D, Sulaiman I, Gunaratnam C, Branagan P, O'Brien ME, Morgan RK, Costello RW, Hurley K, Walsh S, de Barra E, McNally C, McConkey S, Boland F, Galvin S, Kiernan F, O'Rourke J, Dwyer R, Power M, Geoghegan P, Larkin C, O'Leary RA, Freeman J, Gaffney A, Marsh B, Curley GF, McElvaney NG (2020) Characterization of the inflammatory response to severe COVID-19 illness. Am J Respir Crit Care Med 202(6): 812−821
McGonagle D, Sharif K, O'Regan A, Bridgewood C (2020) The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 19(6): 102537. https://doi.org/10.1016/j.autrev.2020.102537
Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ (2020) COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395(10229): 1033−1034
Michot JM, Albiges L, Chaput N, Saada V, Pommeret F, Griscelli F, Balleyguier C, Besse B, Marabelle A, Netzer F, Merad M, Robert C, Barlesi F, Gachot B, Stoclin A (2020) Tocilizumab, an anti-IL-6 receptor antibody, to treat COVID-19-related respiratory failure: a case report. Ann Oncol 31(7): 961−964
Miossec P, Kolls JKJNRDD (2012) Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 11(10): 763−776
Monteleone G, Sarzi-Puttini PC, Ardizzone S (2020) Preventing COVID-19-induced pneumonia with anticytokine therapy. Lancet Rheumatol 2(5): e255−e256. https://doi.org/10.1016/S2665-9913(20)30092-8
Morena V, Milazzo L, Oreni L, Bestetti G, Fossali T, Bassoli C, Torre A, Cossu MV, Minari C, Ballone E, Perotti A, Mileto D, Niero F, Merli S, Foschi A, Vimercati S, Rizzardini G, Sollima S, Bradanini L, Galimberti L, Colombo R, Micheli V, Negri C, Ridolfo AL, Meroni L, Galli M, Antinori S, Corbellino M (2020) Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy. Eur J Intern Med 76: 36−42
Müllberg J, Schooltink H, Stoyan T, Günther M, Graeve L, Buse G, Mackiewicz A, Heinrich PC, Rose-John S (1993) The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol 23(2): 473−480
Navarro G, Taroumian S, Barroso N, Duan L, Furst D (2014) Tocilizumab in rheumatoid arthritis: a meta-analysis of efficacy and selected clinical conundrums. Semin Arthritis Rheum 43(4): 458−469
Ogata A, Kato Y, Higa S, Yoshizaki K (2019) IL-6 inhibitor for the treatment of rheumatoid arthritis: a comprehensive review. Mod Rheumatol 29(2): 258−267
Ortiz-Martinez Y (2020) Tocilizumab: a new opportunity in the possible therapeutic arsenal against COVID-19. Travel Med Infect Dis 37: 101678. https://doi.org/10.1016/j.tmaid.2020.101678
Palanques-Pastor T, López-Briz E, Poveda Andrés JL (2020) Involvement of interleukin 6 in SARS-CoV-2 infection: siltuximab as a therapeutic option against COVID-19. Eur J Hosp Pharm 27(5): 297−298
Pawar A, Desai RJ, Gautam N, Kim SC (2020) Risk of admission to hospital for serious infection after initiating tofacitinib versus biologic DMARDs in patients with rheumatoid arthritis: a multidatabase cohort study. Lancet Rheumatol 2(2): e84−e98. https://doi.org/10.1016/S2665-9913(19)30137-7
Petrosillo N, Viceconte G, Ergonul O, Ippolito G, Petersen E (2020) COVID-19, SARS and MERS: are they closely related? Clin Microbiol Infect 26(6): 729−734
Qiao R, Dong B (2020) From SARS, MERS to COVID-19 — Known an Unknown. J Modern Clin Med 46(03): 221−224
Quartuccio L, Sonaglia A, Pecori D, Peghin M, Fabris M, Tascini C, De Vita S (2020) Higher levels of IL-6 early after tocilizumab distinguish survivors from nonsurvivors in COVID-19 pneumonia: a possible indication for deeper targeting of IL-6. J Med Virol 92(11): 2852−2856
Renu K, Prasanna PL, Valsala Gopalakrishnan A (2020) Coronaviruses pathogenesis, comorbidities and multi-organ damage - a review. Life Sci 255: 117839. https://doi.org/10.1016/j.lfs.2020.117839
Rose-John S, Heinrich PC (1994) Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 300(Pt 2): 281−290
Rose-John S, Waetzig GH, Scheller J, Grötzinger J, Seegert D (2007) The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin Ther Targets 11(5): 613−624
Ruan Q, Yang K, Wang W, Jiang L, Song J (2020) Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med 46(5): 846−848
Russell CD, Millar JE, Baillie JK (2020) Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 395(10223): 473−475
Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S (2011) The pro- and anti-inflammatory properties of the cytokine interleukin-6. BBA-Molr Cell Res 1813(5): 878−888
Sciascia S, Aprà F, Baffa A, Baldovino S, Boaro D, Boero R, Bonora S, Calcagno A, Cecchi I, Cinnirella G, Converso M, Cozzi M, Crosasso P, De Iaco F, Di Perri G, Eandi M, Fenoglio R, Giusti M, Imperiale D, Imperiale G, Livigni S, Manno E, Massara C, Milone V, Natale G, Navarra M, Oddone V, Osella S, Piccioni P, Radin M, Roccatello D, Rossi D (2020) Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol 38(3): 529−532
Sharan Tripathi S, Mishra V, Shukla M, Verma M, Chaudhury BP, Kumar P, Chhabra JK, Pandey HP, Paul B (2010) IL-6 receptor-mediated lung Th2 cytokine networking in silica-induced pulmonary fibrosis. ArchToxicol 84(12): 947−955
Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler HJ, Schlößer HA, Schlaak M, Kochanek M, Böll B, von Bergwelt-Baildon MS (2018) Cytokine release syndrome. J Immunother Cancer 6(1): 56. https://doi.org/10.1186/s40425-018-0343-9
Simpson RJ, Hammacher A, Smith DK, Matthews JM, Ward LD (1997) Interleukin-6: structure-function relationships. Protein Sci 6(5): 929−955
Soldati G, Smargiassi A, Inchingolo R, Buonsenso D, Perrone T, Briganti DF, Perlini S, Torri E, Mariani A, Mossolani EE, Tursi F, Mento F, Demi L (2020) Proposal for international standardization of the use of lung ultrasound for patients with COVID‐19. J Ultrasound Med 39(7): 1413−1419
Soy M, Keser G, Atagündüz P, Tabak F, Atagündüz I, Kayhan S (2020) Cytokine storm in COVID-19: pathogenesis and overview of anti-inflammatory agents used in treatment. Clin Rheumatol 39(7): 2085−2094
Strohbehn GW, Heiss BL, Rouhani SJ, Trujillo JA, Yu J, Kacew AJ, Higgs EF, Bloodworth JC, Cabanov A, Wright RC, Koziol AK, Weiss A, Danahey K, Karrison TG, Edens CC, Ventura IB, Pettit NN, Patel BK, Pisano J, Strek ME, Gajewski TF, Ratain MJ, Reid PD (2020) COVIDOSE: Low-dose tocilizumab in the treatment of Covid-19. medRxiv. https://doi.org/10.1101/2020.07.20.20157503
Tanaka T (2015) IL-6 blockade therapy for inflammatory diseases: current perspectives and future directions. Nihon Rinsho Men'eki Gakkai kaishi 38(6): 433−442
Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Katze MGJM, Mmbr MBR (2012) Into the eye of the cytokine storm. Microbiol Mol Biol Rev 76(1): 16−32
Tobaiqy M, Qashqary M, Al-Dahery S, Mujallad A, Hershan AA, Kamal MA, Helmi N (2020) Therapeutic management of patients with COVID-19: a systematic review. Infect Prev Pract 2(3): 100061. https://doi.org/10.1016/j.infpip.2020.100061
Toniati P, Piva S, Cattalini M, Garrafa E, Regola F, Castelli F, Franceschini F, Airo P, Bazzani C, Beindorf EA, Berlendis M, Bezzi M, Bossini N, Castellano M, Cattaneo S, Cavazzana I, Contessi GB, Crippa M, Delbarba A, De Peri E, Faletti A, Filippini M, Filippini M, Frassi M, Gaggiotti M, Gorla R, Lanspa M, Lorenzotti S, Marino R, Maroldi R, Metra M, Matteelli A, Modina D, Moioli G, Montani G, Muiesan ML, Odolini S, Peli E, Pesenti S, Pezzoli MC, Pirola I, Pozzi A, Proto A, Rasulo FA, Renisi G, Ricci C, Rizzoni D, Romanelli G, Rossi M, Salvetti M, Scolari F, Signorini L, Taglietti M, Tomasoni G, Tomasoni LR, Turla F, Valsecchi A, Zani D, Zuccala F, Zunica F, Foca E, Andreoli L, Latronico N (2020) Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: a single center study of 100 patients in Brescia, Italy. Autoimmun Rev 19(7): 102568. https://doi.org/10.1016/j.autrev.2020.102568
Tseng WP, Su CM, Tang CH (2010) FAK activation is required for TNF-alpha-induced IL-6 production in myoblasts. J Cell Physiol 223(2): 389−396
Urashima M, Chauhan D, Hatziyanni M, Ogata A, Hollenbaugh D, Aruffo A, Anderson KC (1996) CD40 ligand triggers interleukin-6 mediated B cell differentiation. Leuk Res 20(6): 507−515
Varghese JN, Moritz RL, Lou M-Z, van Donkelaar A, Ji H, Ivancic N, Branson KM, Hall NE, Simpson RJ (2002) Structure of the extracellular domains of the human interleukin-6 receptor α-chain. Proc Natl Acad Sci USA 99(25): 15959−15964
Velazquez-Salinas L, Verdugo-Rodriguez A, Rodriguez LL, Borca MV (2019) The role of interleukin 6 during viral infections. Front Microbiol 10: 1057. https://doi.org/10.3389/fmicb.2019.01057
Vilchez-Oya F, Pros A, Carrion-Barbera I, Meraz-Ostiz JA, Salman-Monte TC, Perez-Garcia C (2020) Tocilizumab may induce secondary hypogammaglobulinaemia. A retrospective case series of 42 patients. Joint Bone Spine 87(5): 503−505
Vollmer P, Walev I, Rose-John S, Bhakdi S (1996) Novel pathogenic mechanism of microbial metalloproteinases: liberation of membrane-anchored molecules in biologically active form exemplified by studies with the human interleukin-6 receptor. Infect Immun 64(9): 3646−3651
Wan S, Yi Q, Fan S, Lv J, Zhang X, Guo L, Lang C, Xiao Q, Xiao K, Yi Z, Qiang M, Xiang J, Zhang B, Chen Y (2020) Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). medRxiv. https://doi.org/10.1101/2020.02.10.20021832
Wang W-K, Chen S-Y , Liu I-J, Kao C-L , Chen H-L, Chiang B-L, Wang J-T , Sheng W-H , Hsueh P-R , Yang C-F , Yang P-C , Chang S-C (2004) Temporal relationship of viral load, ribavirin, interleukin (IL)—6, IL-8, and clinical progression in patients with severe acute respiratory syndrome. Clin Infect Dis 39(7): 1071−1075
Xiaoling X, Mingfeng H, Tiantian L, Wei S, Dongsheng W, Binqing F, Yonggang Z, Xiaohu Z, Yun Y, Xiuyong L, Xiaohua Z, Aijun P, Haiming W (2020) Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA 117(20): 10970−10975
Yang R, Masters AR, Fortner KA, Champagne DP, Rincon MJJoEM (2016) IL-6 promotes the differentiation of a subset of naive CD8+ T cells into IL-21–producing B helper CD8+ T cells. J Exp Med 213(11): 2281−2291
Yang X-Y, Song J, Hou S-K, Fan H-J, Lv Q, Liu Z-Q, Ding H, Zhang Y-Z, Liu J-Y, Dong W-L, Wang X (2020) Ulinastatin ameliorates acute kidney injury induced by crush syndrome inflammation by modulating Th17/Treg cells. Int Immunopharmacol 81: 106265. https://doi.org/10.1016/j.intimp.2020.106265
Ye Q, Wang B, Mao J (2020) The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19. J Infect 80(6): 607−613
Yin Y, Wunderink RG (2018) MERS, SARS and other coronaviruses as causes of pneumonia. Respirology 23(2): 130−137
Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M, Tomiita M, Nishimoto N, Kishimoto T (2008) Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 371(9617): 998−1006
Zha L, Li S, Pan L, Tefsen B, Li Y, French N, Chen L, Yang G, Villanueva EV (2020) Corticosteroid treatment of patients with coronavirus disease 2019 (COVID-19). Med J Aust 212(9): 416−420
Zhang C, Wu Z, Li JW, Zhao H, Wang GQ (2020a) Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrob Agents 55(5): 105954. https://doi.org/10.1016/j.ijantimicag.2020.105954
Zhang Y, Gao Y, Qiao L, Wang W, Chen D (2020b) Inflammatory response cells during acute respiratory distress syndrome in patients with coronavirus disease 2019 (COVID-19). Ann Intern Med 173(5): 402−404
Zhao J, Li K, Wohlford-Lenane C, Agnihothram SS, Fett C, Zhao J, Gale MJ Jr., Baric RS, Enjuanes L, Gallagher T, McCray PB Jr., Perlman S (2014) Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci USA 111(13): 4970−4975
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B (2020) Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 395(10229): 1054−1062
Zohlnhöfer D, Graeve L, Rose-John S, Schooltink H, Dittrich E, Heinrich PC (1992) The hepatic interleukin-6 receptor. Down-regulation of the interleukin-6 binding subunit (gp80) by its ligand. FEBS Lett 306(2-3): 219−222
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.