Interleukin‑6 signalling as a valuable cornerstone for molecular medicine (Review)

Trovato,Maria; Sciacchitano,Salvatore; Facciolà,Alessio; Valenti,Andrea; Visalli,Giuseppa; Di Pietro,Angela

doi:10.3892/ijmm.2021.4940

Interleukin‑6 signalling as a valuable cornerstone for molecular medicine (Review)

Authors:
- Maria Trovato
- Salvatore Sciacchitano
- Alessio Facciolà
- Andrea Valenti
- Giuseppa Visalli
- Angela Di Pietro
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Affiliations: Department of Clinical and Experimental Medicine, University Hospital, I‑98125 Messina, Italy, Department of Clinical and Molecular Medicine, Sapienza University, I‑00189 Rome, Italy, Department of Biomedical and Dental Sciences and Morphofunctional Imaging, Policlinico Universitario, I‑98125 Messina, Italy
Published online on: April 16, 2021 https://doi.org/10.3892/ijmm.2021.4940
Article Number: 107
Copyright: © Trovato et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The biological abilities of interleukin‑6 (IL‑6) have been under investigation for nearly 40 years. IL‑6 works through an interaction with the complex peptide IL‑6 receptor (IL‑6R). IL‑6 is built with four α‑chain nanostructures, while two different chains, IL‑6Rα (gp80) and gp130/IL6β (gp130), are included in IL‑6R. The three‑dimensional shapes of the six chains composing the IL‑6/IL‑6R complex are the basis for the nanomolecular roles of IL‑6 signalling. Genes, pseudogenes and competitive endogenous RNAs of IL‑6 have been identified. In the present review, the roles played by miRNA in the post‑transcriptional regulation of IL‑6 expression are evaluated. mRNAs are absorbed via the ‘sponge’ effect to dynamically balance mRNA levels and this has been assessed with regard to IL‑6 transcription efficiency. According to current knowledge on molecular and nanomolecular structures involved in active IL‑6 signalling, two different IL‑6 models have been proposed. IL‑6 mainly has functions in inflammatory processes, as well as in cognitive activities. Furthermore, the abnormal production of IL‑6 has been found in patients with severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2; also known as COVID‑19). In the present review, both inflammatory and cognitive IL‑6 models were analysed by evaluating the cytological and histological locations of IL‑6 signalling. The goal of this review was to illustrate the roles of the classic and trans‑signalling IL‑6 pathways in endocrine glands such as the thyroid and in the central nervous system. Specifically, autoimmune thyroid diseases, disorders of cognitive processes and SARS‑CoV‑2 virus infection have been examined to determine the contribution of IL‑6 to these disease states.

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1	Schimpl A and Wecker E: Replacement of T cell function by a T cell product. Nat New Biol. 237:15–17. 1972. View Article : Google Scholar : PubMed/NCBI
2	Hirano T: Revisiting the 1986 molecular cloning of interleukin 6. Front Immunol. 5:4562014. View Article : Google Scholar : PubMed/NCBI
3	Hirano T, Taga T, Nakano N, Yasukawa K, Kashiwamura S, Shimizu K, Nakajima K, Pyun KH and Kishimoto T: Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci USA. 82:5490–5494. 1985. View Article : Google Scholar : PubMed/NCBI
4	Sehgal PB, Grieninger G and Tosato G: Regulation of the acute phase and immune responses: Interleukin-6. Ann N Y Acad Sci. 557:1–583. 1989.
5	Sehgal PB, Zilberstein A, Ruggieri RM, May LT, Ferguson-Smith A, Slate DL, Revel M and Ruddle FH: Human chromosome 7 carries the beta 2 interferon gene. Proc Natl Acad Sci USA. 83:5219–5222. 1986. View Article : Google Scholar : PubMed/NCBI
6	Sutherland GR, Baker E, Callen DF, Hyland VJ, Wong G, Clark S, Jones SS, Eglinton LK, Shannon MF, Lopez AF, et al: Interleukin 4 is at 5q31 and interleukin 6 is at 7p15. Hum Genet. 79:335–337. 1988. View Article : Google Scholar : PubMed/NCBI
7	Somers W, Stahl M and Seehra JS: 1.9 A crystal structure of interleukin 6: Implications for a novel mode of receptor dimerization and signaling. EMBO J. 16:989–997. 1997. View Article : Google Scholar : PubMed/NCBI
8	Zhou L, Zheng Y, Tian T, Liu K, Wang M, Lin S, Deng Y, Dai C, Xu P, Hao Q, et al: Associations of interleukin-6 gene polymorphisms with cancer risk: Evidence based on 49,408 cancer cases and 61,790 controls. Gene. 670:136–147. 2018. View Article : Google Scholar : PubMed/NCBI
9	Simpson RJ, Hammacher A, Smith DK, Matthews JM and Ward LD: Interleukin-6: Structure-function relationships. Protein Sci. 6:929–955. 1997. View Article : Google Scholar : PubMed/NCBI
10	Hirano T: Interleukin 6 and its receptor: Ten years later. Int Rev Immunol. 16:249–284. 1998. View Article : Google Scholar : PubMed/NCBI
11	Hunter CA and Jones SA: IL-6 as a keystone cytokine in health and disease. Nat Immunol. 16:448–457. 2015. View Article : Google Scholar : PubMed/NCBI
12	Sumikawa H, Fukuhara K, Suzuki E, Matsuo Y and Nishikawa K: Tertiary structural models for human interleukin-6 and evaluation by a sequence-structure compatibility method and NMR experimental information. FEBS Lett. 404:234–240. 1997. View Article : Google Scholar : PubMed/NCBI
13	Heinrich PC, Castell JV and Andus T: Interleukin-6 and the acute phase response. Biochem J. 265:621–636. 1990. View Article : Google Scholar : PubMed/NCBI
14	Bazan JF: Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA. 87:6934–6938. 1990. View Article : Google Scholar : PubMed/NCBI
15	Sakakibara S and Tosato G: Viral Interleukin-6: Role in Kaposi's sarcoma-associated herpesvirus: Associated malignancies. J Interferon Cytokine Res. 31:791–801. 2011. View Article : Google Scholar : PubMed/NCBI
16	Yamasaki K, Taga T, Hirata Y, Yawata H, Kawanishi Y, Seed B, Taniguchi T, Hirano T and Kishimoto T: Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 241:825–828. 1988. View Article : Google Scholar : PubMed/NCBI
17	Hibi M, Murakami M, Saito M, Hirano T, Taga T and Kishimoto T: Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 63:1149–1157. 1990. View Article : Google Scholar : PubMed/NCBI
18	Kluck PM, Wiegant J, Jansen RP, Bolk MW, Raap AK, Willemze R and Landegent JE: The human interleukin-6 receptor alpha chain gene is localized on chromosome 1 band q21. Hum Genet. 90:542–544. 1993. View Article : Google Scholar : PubMed/NCBI
19	Rodriguez C, Grosgeorge J, Nguyen VC, Gaudray P and Theillet C: Human gp130 transducer chain gene (IL6ST) is localized to chromosome band 5q11 and possesses a pseudogene on chromosome band 17p11. Cytogenet Cell Genet. 70:64–67. 1995. View Article : Google Scholar : PubMed/NCBI
20	Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T and Kishimoto T: Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 58:573–581. 1989. View Article : Google Scholar : PubMed/NCBI
21	Boulanger MJ, Chow DC, Brevnova EE and Garcia KC: Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science. 300:2101–2104. 2003. View Article : Google Scholar : PubMed/NCBI
22	Lacroix M, Rousseau F, Guilhot F, Malinge P, Magistrelli G, Herren S, Jones SA, Jones GW, Scheller J, Lissilaa R, et al: Novel insights into interleukin 6 (IL-6) Cis- and trans-signaling pathways by differentially manipulating the assembly of the IL-6 signaling complex. J Biol Chem. 290:26943–26953. 2015. View Article : Google Scholar : PubMed/NCBI
23	Trovato MC, Andronico D, Sciacchitano S, Ruggeri RM, Picerno I, Di Pietro A and Visalli G: Nanostructures: Between natural environment and medical practice. Rev Environ Health. 33:295–307. 2018. View Article : Google Scholar : PubMed/NCBI
24	Weidle UH, Klostermann S, Eggle D and Krüger A: Interleukin 6/interleukin 6 receptor interaction and its role as a therapeutic target for treatment of cachexia and cancer. Cancer Genomics Proteomics. 7:287–302. 2010.PubMed/NCBI
25	Heinrich PC, Behrmann I, Haan S, Hermanns HM, Müller-Newen G and Schaper F: Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J. 374:1–20. 2003. View Article : Google Scholar : PubMed/NCBI
26	Scheller J, Chalaris A, Schmidt-Arras D and Rose-John S: The pro- and anti-inflammatory properties of the cytokine inter-leukin-6. Biochim Biophys Acta. 1813:878–888. 2011. View Article : Google Scholar : PubMed/NCBI
27	An Y, Furber KL and Ji S: Pseudogenes regulate parental gene expression via ceRNA network. J Cell Mol Med. 21:185–192. 2017. View Article : Google Scholar
28	Kuscuoglu D, Janciauskiene S, Hamesch K, Haybaeck J, Trautwein C and Strnad P: Liver-master and servant of serum proteome. J Hepatol. 69:512–524. 2018. View Article : Google Scholar : PubMed/NCBI
29	Tuck AC and Tollervey D: A transcriptome-wide atlas of RNP composition reveals diverse classes of mRNAs and lncRNAs. Cell. 154:996–1009. 2013. View Article : Google Scholar : PubMed/NCBI
30	St Laurent G, Wahlestedt C and Kapranov P: The landscape of long noncoding RNA classification. Trends Genet. 31:239–251. 2015. View Article : Google Scholar : PubMed/NCBI
31	Pink RC, Wicks K, Caley DP, Punch EK, Jacobs L and Carter DR: Pseudogenes: Pseudo-functional or key regulators in health and disease? RNA. 17:792–798. 2011. View Article : Google Scholar : PubMed/NCBI
32	Salmena L, Poliseno L, Tay Y, Kats L and Pandolfi PP: A ceRNA hypothesis: The Rosetta stone of a hidden RNA language? Cell. 146:353–358. 2011. View Article : Google Scholar : PubMed/NCBI
33	van Rij RP and Andino R: The silent treatment: RNAi as a defense against virus infection in mammals. Trends Biotechnol. 24:186–193. 2006. View Article : Google Scholar : PubMed/NCBI
34	Lavra L, Ulivieri A, Dominici R, Trovato MC, Bartolazzi A, Soddu S and Sciacchitano S: Analysis of the role of p53 and galectin-3 in proliferation and apoptosis of thyroid carcinoma cell lines by specific RNA interference experiments. Biomed Pharmacother. 60:4912006. View Article : Google Scholar
35	Cecchinelli B, Lavra L, Rinaldo C, Iacovelli S, Gurtner A, Gasbarri A, Ulivieri A, Del Prete F, Trovato M, Piaggio G, et al: Repression of the antiapoptotic molecule Galectin-3 by homeodomain-interacting protein kinase 2-activated p53 is required for p53-Induced apoptosis. Mol Cell Biol. 26:4746–4757. 2006. View Article : Google Scholar : PubMed/NCBI
36	Bautista RR, Gómez AO, Miranda AH, Dehesa AZ, Villarreal-Garza C, Ávila-Moreno F and Arrieta O: Correction to: Long non-coding RNAs: Implications in targeted diagnoses, prognosis, and improved therapeutic strategies in human non- and triple-negative breast cancer. Clin Epigenetics. 10:1062018. View Article : Google Scholar : PubMed/NCBI
37	Hosseinahli N, Aghapour M, Duijf PHG and Baradaran B: Treating cancer with microRNA replacement therapy: A literature review. J Cell Physiol. 233:5574–5588. 2018. View Article : Google Scholar : PubMed/NCBI
38	Huang HC, Yu HR, Hsu TY, Chen IL, Huang HC, Chang JC and Yang KD: MicroRNA-142-3p and let-7g negatively regulates augmented IL-6 production in neonatal polymorphonuclear leukocytes. Int J Biol Sci. 13:690–700. 2017. View Article : Google Scholar : PubMed/NCBI
39	Liao YC, Wang YS, Guo YC, Lin WL, Chang MH and Juo SH: Let-7g improves multiple endothelial functions through targeting transforming growth factor-beta and SIRT-1 signaling. J Am Coll Cardiol. 63:1685–1694. 2014. View Article : Google Scholar
40	Johnson CD, Esquela-Kerscher A, Stefani G, Byrom M, Kelnar K, Ovcharenko D, Wilson M, Wang X, Shelton J, Shingara J, et al: The let-7 MicroRNA represses cell proliferation pathways in human cells. Cancer Res. 67:7713–7722. 2007. View Article : Google Scholar : PubMed/NCBI
41	Gao X, Xu W, Lu T, Zhou J, Ge X and Hua D: MicroRNA-142-3p promotes cellular invasion of colorectal cancer cells by activation of RAC1. Technol Cancer Res Treat. 17:15330338187905082018. View Article : Google Scholar : PubMed/NCBI
42	Sun Y, Varambally S, Maher CA, Cao Q, Chockley P, Toubai T, Malter C, Nieves E, Tawara I, Wang Y, et al: Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality. Blood. 117:6172–6183. 2011. View Article : Google Scholar : PubMed/NCBI
43	Sung SY, Liao CH, Wu HP, Hsiao WC, Wu IH, Jinpu Yu, Lin SH and Hsieh CL: Loss of let-7 microRNA upregulates IL-6 in bone marrow-derived mesenchymal stem cells triggering a reactive stromal response to prostate cancer. PLoS One. 8:e716372013. View Article : Google Scholar : PubMed/NCBI
44	Selzner N, Selzner M, Odermatt B, Tian Y, Van Rooijen N and Clavien PA: ICAM-1 triggers liver regeneration through leukocyte recruitment and Kupffer cell-dependent release of TNF-alpha/IL-6 in mice. Gastroenterology. 124:692–700. 2003. View Article : Google Scholar : PubMed/NCBI
45	Yoshiya S, Shirabe K, Imai D, Toshima T, Yamashita Y, Ikegami T, Okano S, Yoshizumi T, Kawanaka H and Maehara Y: Blockade of the apelin-APJ system promotes mouse liver regeneration by activating Kupffer cells after partial hepatectomy. J Gastroenterol. 50:573–582. 2015. View Article : Google Scholar
46	Kishimoto T: Interleukin-6: From basic science to medicine-40 years in immunology. Annu Rev Immunol. 23:1–21. 2005. View Article : Google Scholar
47	Papanicolaou DA and Vgontzas AN: Interleukin-6: The endocrine cytokine. J Clin Endocrinol Metab. 85:1331–1333. 2000. View Article : Google Scholar : PubMed/NCBI
48	Ruggeri RM, Sciacchitano S, Vitale A, Cardelli P, Galletti M, Vitarelli E, Barresi G, Benvenga S, Trimarchi F and Trovato M: Serum hepatocyte growth factor is increased in hashimoto's thyroiditis whether or not associated with nodular goiter as compared with healthy non goitrous individuals. J Endocrinol Invest. 32:465–469. 2009. View Article : Google Scholar : PubMed/NCBI
49	Trovato M, Ruggeri RM, Sciacchitano S, Vicchio TM, Picerno I, Pellicanò G, Valenti A and Visalli G: Serum interleukin-6 levels are increased in HIV-infected patients that develop autoimmune disease during long-term follow-up. Immunobiology. 223:264–268. 2018. View Article : Google Scholar
50	Ruggeri RM, Villari D, Simone A, Scarfi R, Attard M, Orlandi F, Barresi G, Trimarchi F, Trovato M and Benvenga S: Co-expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) in thyroid nodules is associated with co-expression of CD30 ligand/CD30 receptor. J Endocrinol Invest. 25:959–966. 2002. View Article : Google Scholar
51	Trovato M, Grosso M, Vitarelli E, Ruggeri RM, Alesci S, Trimarchi F, Barresi G and Benvenga S: Distinctive expression of STAT3 in papillary thyroid carcinomas and a subset of follicular adenomas. Histol Histopathol. 18:393–399. 2003.PubMed/NCBI
52	Ruggeri RM, Barresi G, Sciacchitano S, Trimarchi F, Benvenga S and Trovato M: Immunoexpression of the CD30 ligand/CD30 and IL-6/IL-6R signals in thyroid autoimmune diseases. Histol Histopathol. 21:249–256. 2006.
53	Trovato M: A historical excursus of diagnostic methods for Hashimoto thyroiditis and Graves' disease. Gazz Med Ital Arch Sci Med. 179:479–485. 2020. View Article : Google Scholar
54	Elsabahy M and Wooley KL: Cytokines as biomarkers of nanoparticle immunotoxicity. Chem Soc Rev. 42:5552–5576. 2013. View Article : Google Scholar : PubMed/NCBI
55	Visalli G, Baluce B, Bertuccio M, Picerno I and Di Pietro A: Mitochondrial-Mediated apoptosis pathway in alveolar epithelial cells exposed to the metals in Combustion-Generated particulate matter. J Toxicol Environ Health A. 78:697–709. 2015. View Article : Google Scholar : PubMed/NCBI
56	Visalli G, Facciolà A, Iannazzo D, Piperno A, Pistone A and Di Pietro A: The role of the iron catalyst in the toxicity of multi-walled carbon nanotubes (MWCNTs). J Trace Elem Med Biol. 43:153–160. 2017. View Article : Google Scholar : PubMed/NCBI
57	Visalli G, Currò M, Iannazzo D, Pistone A, Pruiti Ciarello M, Acri G, Testagrossa B, Bertuccio MP, Squeri R and Di Pietro A: In vitro assessment of neurotoxicity and neuroinflammation of homemade MWCNTs. Environ Toxicol Pharmacol. 56:121–128. 2017. View Article : Google Scholar : PubMed/NCBI
58	Visalli G, Facciolà A, Currò M, Laganà P, La Fauci V, Iannazzo D, Pistone A and Di Pietro A: Mitochondrial impairment induced by sub-chronic exposure to multi-walled carbon nanotubes. Int J Environ Res Public Health. 16:7922019. View Article : Google Scholar :
59	Facciolà A, Visalli G, La Maestra S, Ceccarelli M, D'Aleo F, Nunnari G, Pellicanò GF and Di Pietro A: Carbon nanotubes and central nervous system: Environmental risks, toxicological aspects and future perspectives. Environ Toxicol Pharmacol. 65:23–30. 2019. View Article : Google Scholar
60	Palomäki J, Välimäki E, Sund J, Vippola M, Clausen PA, Jensen KA, Savolainen K, Matikainen S and Alenius H: Long, needle-like carbon nanotubes and asbestos activate the NLRP3 inflammasome through a similar mechanism. ACS Nano. 5:6861–6870. 2011. View Article : Google Scholar : PubMed/NCBI
61	Neagu M, Constantin C, Popescu ID, Zipeto D, Tzanakakis G, Nikitovic D, Fenga C, Stratakis CA, Spandidos DA and Tsatsakis AM: Inflammation and metabolism in cancer cell-mitochondria key player. Front Oncol. 9:3482019. View Article : Google Scholar : PubMed/NCBI
62	Arnoldussen YJ, Skogstad A, Skaug V, Kasem M, Haugen A, Benker N, Weinbruch S, Apte RN and Zienolddiny S: Involvement of IL-1 genes in the cellular responses to carbon nanotube exposure. Cytokine. 73:128–137. 2015. View Article : Google Scholar : PubMed/NCBI
63	Migliore L, Uboldi C, Di Bucchianico S and Coppedè F: Nanomaterials and neurodegeneration. Environ Mol Mutagen. 56:149–170. 2015. View Article : Google Scholar : PubMed/NCBI
64	Bardi G, Nunes A, Gherardini L, Bates K, Al-Jamal KT, Gaillard C, Prato M, Bianco A, Pizzorusso T and Kostarelos K: Functionalized carbon nanotubes in the brain: Cellular internalization and neuroinflammatory responses. PLoS One. 8:e809642013. View Article : Google Scholar : PubMed/NCBI
65	Bussy C, Al-Jamal KT, Boczkowski J, Lanone S, Prato M, Bianco A and Kostarelos K: Microglia determine brain region-specific neurotoxic responses to chemically functionalized carbon nanotubes. ACS Nano. 9:7815–7830. 2015. View Article : Google Scholar : PubMed/NCBI
66	Rothaug M, Becker-Pauly C and Rose-John S: The role of inter-leukin-6 signaling in nervous tissue. Biochim Biophys Acta. 1863:1218–1227. 2016. View Article : Google Scholar : PubMed/NCBI
67	Hu J, Feng X, Valdearcos M, Lutrin D, Uchida Y, Koliwad SK and Maze M: Interleukin-6 is both necessary and sufficient to produce perioperative neurocognitive disorder in mice. Br J Anaesth. 120:537–545. 2018. View Article : Google Scholar : PubMed/NCBI
68	Fenga C, Gangemi S, Di Salvatore V, Falzone L and Libra M: Immunological effects of occupational exposure to lead (Review). Mol Med Rep. 15:3355–3360. 2017. View Article : Google Scholar : PubMed/NCBI
69	Gangemi S, Gofita E, Costa C, Teodoro M, Briguglio G, Nikitovic D, Tzanakakis G, Tsatsakis AM, Wilks MF, Spandidos DA and Fenga C: Occupational and environmental exposure to pesticides and cytokine pathways in chronic diseases (Review). Int J Mol Med. 38:1012–1020. 2016. View Article : Google Scholar : PubMed/NCBI
70	Shahpiri Z, Bahramsoltani R, Hosein Farzaei M, Farzaei F and Rahimi R: Phytochemicals as future drugs for Parkinson's disease: A comprehensive review. Rev Neurosci. 27:651–668. 2016. View Article : Google Scholar : PubMed/NCBI
71	Ardah MT, Bharathan G, Kitada T and Haque ME: Ellagic acid prevents dopamine neuron degeneration from oxidative stress and neuroinflammation in MPTP Model of Parkinson's disease. Biomolecules. 10:15192020. View Article : Google Scholar
72	Gadient RA and Otten U: Expression of interleukin-6 (IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat brain during postnatal development. Brain Res. 637:10–14. 1994. View Article : Google Scholar : PubMed/NCBI
73	Marsland AL, Gianaros PJ, Abramowitch SM, Manuck SB and Hariri AR: Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults. Biol Psychiatry. 64:484–490. 2008. View Article : Google Scholar : PubMed/NCBI
74	MacQueen GM, Campbell S, McEwen BS, Macdonald K, Amano S, Joffe RT, Nahmias C and Young LT: Course of illness, hippocampal function, and hippocampal volume in major depression. Proc Natl Acad Sci USA. 100:1387–1392. 2003. View Article : Google Scholar : PubMed/NCBI
75	Baune BT, Konrad C, Grotegerd D, Suslow T, Birosova E, Ohrmann P, Bauer J, Arolt V, Heindel W, Domschke K, et al: Interleukin-6 gene (IL-6): A possible role in brain morphology in the healthy adult brain. J Neuroinflammation. 9:1252012. View Article : Google Scholar : PubMed/NCBI
76	Campbell IL, Abraham CR, Masliah E, Kemper P, Inglis JD, Oldstone MB and Mucke L: Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc Natl Acad Sci USA. 90:10061–10065. 1993. View Article : Google Scholar : PubMed/NCBI
77	Campbell IL, Erta M, Lim SL, Frausto R, May U, Rose-John S, Scheller J and Hidalgo J: Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain. J Neurosci. 34:2503–2513. 2014. View Article : Google Scholar : PubMed/NCBI
78	Chucair-Elliott AJ, Conrady C, Zheng M, Kroll CM, Lane TE and Carr DJ: Microglia-induced IL-6 protects against neuronal loss following HSV-1 infection of neural progenitor cells. Glia. 62:1418–1434. 2014. View Article : Google Scholar : PubMed/NCBI
79	Chomarat P, Banchereau J, Davoust J and Palucka AK: IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol. 1:510–514. 2000. View Article : Google Scholar
80	Urashima M, Chauhan D, Hatziyanni M, Ogata A, Hollenbaugh D, Aruffo A and Anderson KC: CD40 ligand triggers interleukin-6 mediated B cell differentiation. Leuk Res. 20:507–515. 1996. View Article : Google Scholar : PubMed/NCBI
81	Yang R, Masters AR, Fortner KA, Champagne DP, Yanguas-Casás N, Silberger DJ, Weaver CT, Haynes L and Rincon M: 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. 213:2281–2291. 2016. View Article : Google Scholar : PubMed/NCBI
82	Diehl S and Rincón M: The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol. 39:531–536. 2002. View Article : Google Scholar : PubMed/NCBI
83	Gubernatorova EO, Gorshkova EA, Polinova AI and Drutskaya MS: IL-6: Relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev. 53:13–24. 2020. View Article : Google Scholar : PubMed/NCBI
84	Xu H, Zhong L, Deng J, Peng J, Dan H, Zeng X, Li T and Chen Q: High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci. 12:82020. View Article : Google Scholar : PubMed/NCBI
85	Rose-John S, Winthrop K and Calabrese L: The role of IL-6 in host defence against infections: Immunobiology and clinical implications. Nat Rev Rheumatol. 13:399–409. 2017. View Article : Google Scholar : PubMed/NCBI
86	Chen G, Wu D, Guo W, Cao Y, Huang D, Wang H, Wang T, Zhang X, Chen H, Yu H, et al: Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest. 130:2620–2629. 2020. View Article : Google Scholar : PubMed/NCBI
87	Ruan Q, Yang K, Wang W, Jiang L and Song J: Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 46:846–848. 2020. View Article : Google Scholar : PubMed/NCBI
88	Abbasifard M and Khorramdelazad H: The bio-mission of interleukin-6 in the pathogenesis of COVID-19: A brief look at potential therapeutic tactics. Life Sci. 257:1180972020. View Article : Google Scholar : PubMed/NCBI
89	Coomes EA and Haghbayan H: Interleukin-6 in Covid-19: A systematic review and meta-analysis. Rev Med Virol. 30:1–9. 2020. View Article : Google Scholar : PubMed/NCBI
90	Zhang J, Hao Y, Ou W, Ming F, Liang G, Qian Y, Cai Q, Dong S, Hu S, Wang W and Wei S: Serum interleukin-6 is an indicator for severity in 901 patients with SARS-CoV-2 infection: A cohort study. J Transl Med. 18:4062020. View Article : Google Scholar : PubMed/NCBI
91	Herold T, Jurinovic V, Arnreich C, Hellmuth JC, von Bergwelt-Baildon M, Klein M and Weinberger T: Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients. medRxiv. https://doi.org/10.1101/2020.04.01.20047381. Accessed April 27, 2020.
92	Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, et al: Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet. 395:1054–1062. 2020. View Article : Google Scholar : PubMed/NCBI
93	Atal S and Fatima Z: IL-6 Inhibitors in the treatment of serious COVID-19: A promising therapy? Pharmaceut Med. 34:223–231. 2020.PubMed/NCBI
94	Xu X, Han M, Li T, Sun W, Wang D, Fu B, Zhou Y, Zheng X, Yang Y, Li X, et al: Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci USA. 117:10970–10975. 2020. View Article : Google Scholar : PubMed/NCBI
95	Fu B, Xu X and Wei H: Why tocilizumab could be an effective treatment for severe COVID-19? J Transl Med. 18:1642020. View Article : Google Scholar : PubMed/NCBI
96	Toniati P, Piva S, Cattalini M, Garrafa E, Regola F, Castelli F, Franceschini F, Airò P, Bazzani C, Beindorf EA, et al: 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. 19:1025682020. View Article : Google Scholar : PubMed/NCBI
97	Issa N, Dumery M, Guisset O, Mourissoux G, Bonnet F and Camou F: Feasibility of tocilizumab in ICU patients with COVID-19. J Med Virol. 93:46–47. 2021. View Article : Google Scholar
98	Alattar R, Ibrahim TBH, Shaar SH, Abdalla S, Shukri K, Daghfal JN, Khatib MY, Aboukamar M, Abukhattab M, Alsoub HA, et al: Tocilizumab for the treatment of severe coronavirus disease 2019. J Med Virol. 92:2042–2049. 2020. View Article : Google Scholar : PubMed/NCBI
99	Della-Torre E, Campochiaro C, Cavalli G, De Luca G, Napolitano A, La Marca S, Boffini N, Da Prat V, Di Terlizzi G, Lanzillotta M, et al: Interleukin-6 blockade with sarilumab in severe COVID-19 pneumonia with systemic hyperinflammation: An open-label cohort study. Ann Rheum Dis. 79:1277–1285. 2020. View Article : Google Scholar : PubMed/NCBI
100	Benucci M, Giannasi G, Cecchini P, Gobbi FL, Damiani A, Grossi V, Infantino M and Manfredi M: COVID-19 pneumonia treated with sarilumab: A clinical series of eight patients. J Med Virol. 92:2368–2370. 2020. View Article : Google Scholar : PubMed/NCBI
101	Palanques-Pastor T, López-Briz E and Poveda Andrés JL: Involvement of interleukin 6 in SARS-CoV-2 infection: Siltuximab as a therapeutic option against COVID-19. Eur J Hosp Pharm. 27:297–298. 2020. View Article : Google Scholar : PubMed/NCBI
102	Gritti G, Raimondi F, Ripamonti D, Riva I, Landi F, Alborghetti L, Frigeni M, Damiani M, Micò C, Fagiuoli S, et al: Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. medRxiv. https://doi.org/10.1101/2020.04.01.20048561.
103	Vaidya G, Czer LSC, Kobashigawa J, Kittleson M, Patel J, Chang D, Kransdorf E, Shikhare A, Tran H, Vo A, et al: Successful treatment of severe COVID-19 pneumonia with clazakizumab in a heart transplant recipient: A case report. Transplant Proc. 52:2711–2714. 2020. View Article : Google Scholar : PubMed/NCBI
104	Stelzer G, Rosen R, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, Stein TI, Nudel R, Lieder I, Mazor Y, et al: The GeneCards suite: From gene data mining to disease genome sequence analysis. Curr Protoc Bioinformatics. 54:1.30.1–1.30.33. 2016. View Article : Google Scholar
105	Hunt SE, McLaren W, Gil L, Thormann A, Schuilenburg H, Sheppard D, Parton A, Armean IM, Trevanion SJ, Flicek P and Cunningham F: Ensembl variation resources. Database (Oxford). 2018:bay1192018. View Article : Google Scholar