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

Niculet,Elena; Chioncel,Valentin; Elisei,Alina M.; Miulescu,Magdalena; Buzia,Olimpia D.; Nwabudike,Lawrence C.; Craescu,Mihaela; Draganescu,Miruna; Bujoreanu,Florin; Marinescu,Elisabeta; Arbune,Manuela; Radaschin,Diana Sabina; Bobeica,Carmen; Nechita,Aurel; Tatu,Alin L.

doi:10.3892/etm.2021.9693

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

Authors:
- Elena Niculet
- Valentin Chioncel
- Alina M. Elisei
- Magdalena Miulescu
- Olimpia D. Buzia
- Lawrence C. Nwabudike
- Mihaela Craescu
- Miruna Draganescu
- Florin Bujoreanu
- Elisabeta Marinescu
- Manuela Arbune
- Diana Sabina Radaschin
- Carmen Bobeica
- Aurel Nechita
- Alin L. Tatu
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Affiliations: Department of Morphological and Functional Sciences, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800010 Galati, Romania, Cardio‑Thoracic Department, ‘Carol Davila’ University of Medicine and Pharmacy, 020021 Bucharest, Romania, Department of Pharmaceutical Sciences, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800010 Galati, Romania, Department of Diabetic Foot Care, ‘Prof. N. Paulescu’ National Institute of Diabetes, 011233 Bucharest, Romania, Clinical Department, Faculty of Medicine and Pharmacy, ‘Dunărea de Jos’ University, 800010 Galati, Romania, Department of Dermatology, ‘Sf. Cuvioasa Parascheva’ Clinical Hospital of Infectious Diseases, 800179 Galati, Romania, Centre of Medical‑Pharmaceutical Research, ‘Dunărea de Jos’ University, 800010 Galati, Romania, Research Center in The Field of Medical and Pharmaceutical Sciences, ReFORM‑UDJ, ‘Dunărea de Jos’ University, 800010 Galati, Romania, Department of Dermato‑Venereology, Doctoral School, University of Medicine and Pharmacy ‘Gr. T. Popa’, 700115 Iași, Romania
Published online on: January 25, 2021 https://doi.org/10.3892/etm.2021.9693
Article Number: 263
Copyright: © Niculet et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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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1	Coughlin BA, Trombley BT and Mohr S: Interleukin-6 (IL-6) mediates protection against glucose toxicity in human Müller cells via activation of VEGF-A signaling. Biochem Biophys Res Commun. 517:227–232. 2019.PubMed/NCBI View Article : Google Scholar
2	Matthes AT, Manfroi B and Huard B: Revisiting IL-6 antagonism in multiple myeloma. Crit Rev Oncol Hematol. 105:1–4. 2016.PubMed/NCBI View Article : Google Scholar
3	Rizzo MD, Crawford RB, Bach A, Sermet S, Amalﬁtano A and Kaminski NE: Imiquimod and interferon-alpha augment monocyte-mediated astrocyte secretion of MCP-1, IL-6 and IP-10 in a human co-culture system. J Neuroimmunol. 333(576969)2019.PubMed/NCBI View Article : Google Scholar
4	Niu X, Chen Y, Qi L, Liang G, Wang Y, Zhang L, Qu Y and Wang W: Hypoxia regulates angeogenic-osteogenic coupling process via up-regulating IL-6 and IL-8 in human osteoblastic cells through hypoxia-inducible factor-1α pathway. Cytokine. 113:117–127. 2019.PubMed/NCBI View Article : Google Scholar
5	Kaur S, Bansal Y, Kumar R and Bansal G: A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors. Bioorg Med Chem. 28(115327)2020.PubMed/NCBI View Article : Google Scholar
6	Choy E and Rose-John S: Interleukin-6 as a multifunctional regulator: Inflammation, immune response, and fibrosis. J Scleroderma Relat Disord. 2 (Suppl 2):S1–S5. 2017.
7	Scheller J, Chalaris A, Schmidt-Arras D and Rose-John S: The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 1813:878–888. 2011.PubMed/NCBI View Article : Google Scholar
8	Prenissl N, Lokau J, Rose-John S, Haybaeck J and Garbers C: Therapeutic blockade of the interleukin-6 receptor (IL-6R) allows sIL-6R generation by proteolytic cleavage. Cytokine. 114:1–5. 2019.PubMed/NCBI View Article : Google Scholar
9	Liang AP, Drazick AT, Gao H and Li Y: Skeletal muscle secretion of IL-6 is muscle type specific: Ex vivo evidence. Biochem Biophys Res Commun. 505:146–150. 2018.PubMed/NCBI View Article : Google Scholar
10	Karthick SR, Sen RK, Gopinathan NR, Dhillon MS, Nada R and Sharma RR: Can IL-6 predict the development of fat embolism in polytrauma? A rabbit model pilot experimental study. J Clin Orthop Trauma. 11 (Suppl 1):S86–S92. 2020.PubMed/NCBI View Article : Google Scholar
11	Del Giudice M and Gangestad SW: Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters. Brain Behav Immun. 70:61–75. 2018.PubMed/NCBI View Article : Google Scholar
12	Bialuk I, Taranta A and Winnicka MM: IL-6 deficiency alters spatial memory in 4- and 24-month-old mice. Neurobiol Learn Mem. 155:21–29. 2018.PubMed/NCBI View Article : Google Scholar
13	Zhou E, Yan F, Li B, Chen M, Tu X, Wu S, Wu H, Wei X, Fu S, Wu L, et al: Molecular and functional characterization of IL-6 receptor (IL-6R) and glycoprotein 130 (gp130) in Nile tilapia (Oreochromis niloticus). Dev Comp Immunol. 106(103629)2020.PubMed/NCBI View Article : Google Scholar
14	Ellingsgaard H, Hojman P and Pedersen BK: Exercise and health-emerging roles of IL-6. Curr Opin Physiol. 10:49–54. 2019.
15	Unver N and McAllister F: IL-6 family cytokines: Key inflammatory mediators as biomarkers and potential therapeutic targets. Cytokine Growth Factor Rev. 41:10–17. 2018.PubMed/NCBI View Article : Google Scholar
16	Dittel LJ, Dittel BN and Brod SA: Ingested ACTH blocks Th17 production by inhibiting GALT IL-6. J Neurol Sci. 409(116602)2020.PubMed/NCBI View Article : Google Scholar
17	Gao S, Hu J, Wu X and Liang Z: PMA treated THP-1-derived-IL-6 promotes EMT of SW48 through STAT3/ERK-dependent activation of Wnt/β-catenin signaling pathway. Biomed Pharmacother. 108:618–624. 2018.PubMed/NCBI View Article : Google Scholar
18	Santhosh Kumar S, Sajeli Begum A, Hira K, Niazi S, Prashantha Kumar BR, Araya H and Fujimoto Y: Structure-based design and synthesis of new 4-methylcoumarin-based lignans as pro-inflammatory cytokines (TNF-α, IL-6 and IL-1β) inhibitors. Bioorg Chem. 89(102991)2019.PubMed/NCBI View Article : Google Scholar
19	Tatu AL, Clatici VG and Nwabudike LC: Rosacea-like demodicosis (but not primary demodicosis) and papulopustular rosacea may be two phenotypes of the same disease-a microbioma, therapeutic and diagnostic tools perspective. J Eur Acad Dermatol Venereol. 33:e46–e47. 2019.PubMed/NCBI View Article : Google Scholar
20	Tatu AL, Ionescu MA and Nwabudike LC: Contact allergy to topical mometasone furoate confirmed by rechallenge and patch test. Am J Ther. 25:e497–e498. 2018.PubMed/NCBI View Article : Google Scholar
21	Brănișteanu DE, Pintilie A, Dimitriu A, Cerbu A, Ciobanu D, Oanţă A and Tatu AL: Clinical, laboratory and therapeutic profile of lichen planus. Rev Med Chir Soc Med Nat. 121:25–32. 2017.
22	Stojanović-Radić Z, Pejčić M, Dimitrijević M, Aleksić A, Anil Kumar NV, Salehi B, Cho CW and Sharifi-Rad J: Piperine-a major principle of black pepper: A review of its bioactivity and studies. Appl Sci. 9(4270)2019.
23	Mihăilă B, Dinică RM, Tatu AL and Buzia OD: New insights in vitiligo treatments using bioactive compounds from Piper nigrum. Exp Ther Med. 17:1039–1044. 2019.PubMed/NCBI View Article : Google Scholar
24	Tatu AL, Ciobotaru OR, Miulescu M, Buzia OD, Elisei AM, Mardare N, Diaconu C, Robu S and Nwabudike LC: Hydrochlorothiazide: Chemical structure, therapeutic, phototoxic and carcinogenetic effects in dermatology. Rev Chim (Bucharest). 69:2110–2114. 2018.
25	Gerber PA, Buhren BA, Steinhoff M and Homey B: Rosacea: The cytokine and chemokine network. J Investig Dermatol Symp Proc. 15:40–47. 2011.PubMed/NCBI View Article : Google Scholar
26	Kim CH, Kim SW and Kim GS: Effects of hydrochlorothiazide and furosemide diuretics on human bone marrow stromal osteoprogenitor cells. Metabolism. 49:17–21. 2000.PubMed/NCBI View Article : Google Scholar
27	Yin M, Li G, Song H and Lin S: Identifying the association between interleukin-6 and lichen planus: A meta-analysis. Biomed Rep. 6:571–575. 2017.PubMed/NCBI View Article : Google Scholar
28	Nibali L, Fedele S, D'Aiuto F and Donos N: Interleukin-6 in oral diseases: A review. Oral Dis. 18:236–243. 2012.PubMed/NCBI View Article : Google Scholar
29	Singh S, Singh U and Pandey SS: Serum concentration of IL-6, IL-2, TNF-α, and IFNγ in vitiligo patients. Indian J Dermatol. 57:12–14. 2012.PubMed/NCBI View Article : Google Scholar
30	Lee HY, Stieger M, Yawalkar N and Kakeda M: Cytokines and chemokines in irritant contact dermatitis. Mediators Inflamm. 2013(916497)2013.PubMed/NCBI View Article : Google Scholar
31	Zeng W, Zhang Y, Duan F, Lin T, Liu X, Li D and Wu K: Lipopolysaccharide enhances human herpesvirus 1 replication and IL-6 release in epithelial cells. Microb Pathog. 140(103961)2020.PubMed/NCBI View Article : Google Scholar
32	Farsakoglu Y, Palomino-Segura M, Latino I, Zanaga S, Chatziandreou N, Pizzagalli DU, Rinaldi A, Bolis M, Sallusto F, Stein JV and Gonzalez SF: Influenza vaccination induces NK-cell-mediated type-II IFN response that regulates humoral immunity in an IL-6-dependent manner. Cell Rep. 26:2307–2315.e5. 2019.PubMed/NCBI View Article : Google Scholar
33	Sun X, Tian Q, Wang L, Xue M and Zhong G: IL-6-mediated signaling pathways limit chlamydia muridarum infection and exacerbate its pathogenicity in the mouse genital tract. Microbes Infect. 19:536–545. 2017.PubMed/NCBI View Article : Google Scholar
34	Muhsin M, Ajendra J, Gentil K, Berbudi A, Neumann AL, Klaas L, Schmidt KE, Hoerauf A and Hübner MP: IL-6 is required for protective immune responses against early filarial infection. Int J Parasitol. 48:925–935. 2018.PubMed/NCBI View Article : Google Scholar
35	Stone SF, Price P, Keane NM, Murray RJ and French MA: Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART. HIV Med. 3:21–27. 2002.PubMed/NCBI View Article : Google Scholar
36	Modrigan M, Draganescu M, Condratovici CP, Pavel LL and Condratovici AP: Clinical personality patterns in young adults with HIV nosocomial infection from the region of southeast Romania. Mater Plast. 54:175–179. 2017.
37	Tiutiuca C, Drăgănescu M, Iancu AV, Chesaru BI, Arbune M, Maftei N and Popescu E: Resistence profile of the isolated bacterial stems in invasive infections in three hospitals from the south-east of Romania. Rev Chim (Bucharest). 68:1122–1125. 2017.
38	Saiki P, Nakajima Y, Van Griensven LJLD and Miyazaki K: Real-time monitoring of IL-6 and IL-10 reporter expression for anti-inflammation activity in live RAW 264.7 cells. Biochem Biophys Res Commun. 505:885–890. 2018.PubMed/NCBI View Article : Google Scholar
39	Shirakura K, Ishiba R, Kashio T, Sakai M, Fukushima Y, Yamamoto N, Manabe S, Shigesada N, Tanaka T, Hino N, et al: Endothelial Robo4 regulates IL-6 production by endothelial cells and monocytes via a crosstalk mechanism in inflammation. Biochem Biophys Res Commun. 495:801–806. 2018.PubMed/NCBI View Article : Google Scholar
40	Uchibori T, Matsuda K, Shimodaira T, Sugano M, Uehara T and Honda T: IL-6 trans-signaling is another pathway to upregulate osteopontin. Cytokine. 90:88–95. 2017.PubMed/NCBI View Article : Google Scholar
41	Atzeni F, Nucera V, Masala IF, Sarzi-Puttini P and Bonitta G: Il-6 involvement in pain, fatigue and mood disorders in rheumatoid arthritis and the effects of Il-6 inhibitor sarilumab. Pharmacol Res. 149(104402)2019.PubMed/NCBI View Article : Google Scholar
42	Gao ST, Xu T, Xun CH, Liang WD, Cao R, Mao C and Sheng WB: Significant association of IL-6-572G/C, IL-6-597G/A, and IL-6-174G/C polymorphisms and susceptibility to lumbar degenerative disease: A meta-analysis. Clin Neurol Neurosurg. 175:40–46. 2018.PubMed/NCBI View Article : Google Scholar
43	Van Gaal LF, Mertens IL and De Block CE: Mechanisms linking obesity with cardiovascular disease. Nature. 444:875–880. 2006.PubMed/NCBI View Article : Google Scholar
44	Eder K, Baffy N, Falus A and Fulop AK: The major inflammatory mediator interleukin-6 and obesity. Inflamm Res. 58:727–736. 2009.PubMed/NCBI View Article : Google Scholar
45	Libby P: Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 32:2045–2051. 2012.PubMed/NCBI View Article : Google Scholar
46	IL6R Genetics Consortium Emerging Risk Factors Collaboration. Sarwar N, Butterworth AS, Freitag DF, Gregson J, Willeit P, Gorman DN, Gao P, Saleheen D, Rendon A, et al: Interleukin-6 receptor pathways in coronary heart disease: A collaborative meta-analysis of 82 studies. Lancet. 379:1205–1213. 2012.PubMed/NCBI View Article : Google Scholar
47	Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. Swerdlow DI, Holmes MV, Kuchenbaecker KB, Engmann JE, Shah T, Sofat R, Guo Y, Chung C, Peasey A, et al: The interleukin-6 receptor as a target for prevention of coronary heart disease: A mendelian randomisation analysis. Lancet. 379:1214–1224. 2012.PubMed/NCBI View Article : Google Scholar
48	Fernandez-Real JM, Vayreda M, Richart C, Gutierrez C, Broch M, Vendrell J and Ricart W: Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women. J Clin Endocrinol Metab. 86:1154–1159. 2001.PubMed/NCBI View Article : Google Scholar
49	Emerging Risk Factors Collaboration. Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R and Danesh J: C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: An individual participant meta-analysis. Lancet. 375:132–140. 2010.PubMed/NCBI View Article : Google Scholar
50	Hartman J and Frishman WH: Inflammation and atherosclerosis: A review of the role of interleukin-6 in the development of atherosclerosis and the potential for targeted drug therapy. Cardiol Rev. 22:147–151. 2014.PubMed/NCBI View Article : Google Scholar
51	Luc G, Bard JM, Juhan-Vague I, Ferrieres J, Evans A, Amouyel P, Arveiler D, Fruchart JC and Ducimetiere P: PRIME Study Group. C-reactive protein, interleukin-6, and fibrinogen as predictors of coronary heart disease: The PRIME study. Arterioscler Thromb Vasc Biol. 23:1255–1261. 2003.PubMed/NCBI View Article : Google Scholar
52	Shlipak MG, Ix JH, Bibbins-Domingo K, Lin F and Whooley MA: Biomarkers to predict recurrent cardiovascular disease: The heart and soul study. Am J Med. 121:50–57. 2008.PubMed/NCBI View Article : Google Scholar
53	Lee JK, Bettencourt R, Brenner D, Le TA, Barrett-Connor E and Loomba R: Association between serum interleukin-6 concentrations and mortality in older adults: The Rancho Bernardo study. PLoS One. 7:1–7. 2012.PubMed/NCBI View Article : Google Scholar
54	Scharnagl H, Stojakovic T, Weihrauch G, Winkelmann BR, Boehm BO and März W: Interleukin-6 is stronger associated with all-cause and cardiovascular mortality than C-reactive protein, serum amyloid and fibrinogen (the luric study). Atheroscler Suppl. 11(42)2010.
55	Fan ZX, Hua Q, Li YP, Liu RK and Yang Z: Interleukin-6, but not soluble adhesion molecules, predicts a subsequent mortality from cardiovascular disease in patients with acute ST-segment elevation myocardial infarction. Cell Biochem Biophys. 61:443–448. 2011.PubMed/NCBI View Article : Google Scholar
56	Zakynthinos E and Pappa N: Inflammatory biomarkers in coronary artery disease. J Cardiol. 53:317–333. 2009.PubMed/NCBI View Article : Google Scholar
57	Yudkin JS, Kumari M, Humphries SE and Mohamed-Ali V: Inflammation, obesity, stress and coronary heart disease: Is interleukin-6 the link? Atherosclerosis. 148:209–214. 2000.PubMed/NCBI View Article : Google Scholar
58	Fontes JA, Rose NR and Čiháková D: The varying faces of IL-6: From cardiac protection to cardiac failure. Cytokine. 74:62–68. 2015.PubMed/NCBI View Article : Google Scholar
59	Baune BT, Rothermundt M, Ladwig KH, Meisinger C and Berger K: Systemic inflammation (interleukin 6) predicts all cause mortality in men: Results from a 9-year follow-up of the MEMO study. Age (Dordr). 33:209–217. 2011.PubMed/NCBI View Article : Google Scholar
60	Fisman EZ, Benderly M, Esper RJ, Behar S, Boyko V, Adler Y, Tanne D, Matas Z and Tenenbaum A: Interleukin-6 and the risk of future cardiovascular events in patients with angina pectoris and/or healed myocardial infarction. Am J Cardiol. 98:14–18. 2006.PubMed/NCBI View Article : Google Scholar
61	Boekholdt SM and Stroes ES: The interleukin-6 pathway and atherosclerosis. Lancet. 379:1176–1178. 2012.PubMed/NCBI View Article : Google Scholar
62	Mendoza CE, Rosado MF and Bernal L: The role of interleukin-6 in cases of cardiac myxoma. Clinical features, immunologic abnormalities, and a possible role in recurrence. Tex Heart Inst J. 28:3–7. 2001.PubMed/NCBI
63	Chae CU, Lee RT, Rifai N and Ridker PM: Blood pressure and inflammation in apparently healthy men. Hypertension. 38:399–403. 2001.PubMed/NCBI View Article : Google Scholar
64	Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB, Wensley F, Higgins JPT, Lennon L, Eiriksdottir G, et al: Long-term interleukin-6 levels and subsequent risk of coronary heart disease: Two new prospective studies and a systematic review. PLoS Med. 5(e78)2008.PubMed/NCBI View Article : Google Scholar
65	Volpato S, Guralnik JM, Ferrucci L, Balfour J, Chaves P, Fried LP and Harris TB: Cardiovascular disease, interleukin-6, and risk of mortality in older women: The women's health and aging study. Circulation. 103:947–953. 2001.PubMed/NCBI View Article : Google Scholar
66	Rao M, Guo D, Perianayagam MC, Tighiouart H, Jaber BL, Pereira BJ and Balakrishnan VS: Plasma interleukin-6 predicts cardiovascular mortality in hemodialysis patients. Am J Kidney Dis. 45:324–333. 2005.PubMed/NCBI View Article : Google Scholar
67	Haugen E, Gan LM, Isic A, Skommevik T and Fu M: Increased interleukin-6 but not tumour necrosis factor-alpha predicts mortality in the population of elderly heart failure patients. Exp Clin Cardiol. 13:19–24. 2008.PubMed/NCBI
68	Panichi V, Maggiore U, Taccola D, Migliori M, Rizza GM, Consani C, Bertini A, Sposini S, Perez-Garcia R, Rindi P, et al: Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients. Nephrol Dial Transplant. 19:1154–1160. 2004.PubMed/NCBI View Article : Google Scholar
69	Candore G, Balistreri CR, Listì F, Grimaldi MP, Vasto S, Colonna-Romano G, Franceschi C, Lio D, Caselli G and Caruso C: Immunogenetics, gender, and longevity. Ann NY Acad Sci. 1089:516–537. 2006.PubMed/NCBI View Article : Google Scholar
70	Frangogiannis NG: The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 11:255–265. 2014.PubMed/NCBI View Article : Google Scholar
71	Groot HE, Al Ali L, van der Horst IC, Schurer RA, van der Werf HW, Lipsic E, van Veldhuisen DJ, Karper JC and van der Harst P: Plasma interleukin 6 levels are associated with cardiac function after ST-elevation myocardial infarction. Clin Res Cardiol. 108:612–621. 2019.PubMed/NCBI View Article : Google Scholar
72	Empana JP, Jouven X, Canoui-Poitrine F, Luc G, Tafflet M, Haas B, Arveiler D, Ferrieres J, Ruidavets JB, Montaye M, et al: C-reactive protein, interleukin 6, fibrinogen and risk of sudden death in European middle-aged men: The PRIME study. Arterioscler Thromb Vasc Biol. 30:2047–2052. 2010.PubMed/NCBI View Article : Google Scholar
73	Samanta A, Cheng G, Davani A, Girgis M, Chen L, Choksi K, Zhao L, Vincent RJ, Hauptman J and Dawn B: Genetic deletion of interleukin-6 attenuates left ventricular dysfunction and remodeling after a reperfused myocardial infarction. Circulation. 130 (Suppl 2)(A15693)2014.
74	Luna JM, Moon YP, Liu KM, Spitalnik S, Paik MC, Cheung K, Sacco RL and Elkind MS: High-sensitivity C-reactive protein and interleukin-6-dominant inflammation and ischemic stroke risk: The northern Manhattan study. Stroke. 45:979–987. 2014.PubMed/NCBI View Article : Google Scholar
75	Bacchiega BC, Bacchiega AB, Usnayo MJ, Bedirian R, Singh G and Pinheiro GD: Interleukin 6 inhibition and coronary artery disease in a high risk population: A prospective community based clinical study. J Am Heart Assoc. 6(e005038)2017.PubMed/NCBI View Article : Google Scholar
76	Tousoulis D, Oikonomou E, Economou EK, Crea F and Kaski JC: Inﬂammatory cytokines in atherosclerosis: Current therapeutic approaches. Eur Heart J. 37:1723–1732. 2016.PubMed/NCBI View Article : Google Scholar
77	Welsh P, Grassia G, Botha S, Sattar N and Mafﬁa P: Targeting inﬂammation to reduce cardiovascular disease risk: A realistic clinical prospect? Br J Pharmacol. 174:3898–3913. 2017.PubMed/NCBI View Article : Google Scholar
78	Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, Siri DA, Tomsic M, Alecock E, Woodworth T and Genovese MC: Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The Ambition study. Ann Rheum Dis. 69:88–96. 2010.PubMed/NCBI View Article : Google Scholar
79	Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, Woodworth T and Alten R: OPTION Investigators. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): A double-blind, placebo-controlled, randomized trial. Lancet. 371:987–997. 2008.PubMed/NCBI View Article : Google Scholar
80	Gabay C, McInnes IB, Kavanaugh A, Tuckwell K, Klearman M, Pulley J and Sattar N: Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. Ann Rheum Dis. 75:1806–1812. 2016.PubMed/NCBI View Article : Google Scholar
81	Gabay C, Emery P, van Vollenhoven R, Dikranian A, Alten R, Pavelka K, Klearman M, Musselman D, Agarwal S, Green J, et al: Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): A randomised, double-blind, controlled phase 4 trial. Lancet. 381:1541–1550. 2013.PubMed/NCBI View Article : Google Scholar
82	Yokoe I, Kobayashi H, Nishiwaki A, Sugiyama K, Nagasawa Y, Karasawa H, Iwata M, Nozaki T, Ikumi N, Inomata H, et al: FRI0204 effect of tocilizumab treatment on QTc interval in patients with rheumatoid arthritis without cardiac symptoms. Ann Rheum Dis. 75 (Suppl 2):S505.1–505. 2016.
83	Kobayashi H, Yokoe I, Nishiwaki A, Sato H and Kobayashi Y: OP0313 effect of tocilizumab on left ventricular function assessed using a comprehensive cardiac magnetic resonance approach in rheumatoid arthritis patients without cardiac symptoms. Ann Rheum Dis. 72 (Suppl 3)(A160)2014.
84	Dello SA, Bloemen JG, van de Poll MC, van Dam RM, Stoot JHMB, van den Broek MAJ, Buurman WA, Bemelmans MHA, Olde Damink SWM and Dejong CHC: Gut and liver handling of interleukin-6 during liver resection in man. HPB (Oxford). 13:324–331. 2011.PubMed/NCBI View Article : Google Scholar
85	Kornasiewicz O, Grąt M, Dudek K, Lewandowski Z, Gorski Z, Zieniewicz K and Krawczyk M: Serum levels of HGF, IL-6, and TGF-α after benign liver tumor resection. Adv Med Sci. 60:173–177. 2015.PubMed/NCBI View Article : Google Scholar
86	Fang C, Cai X, Hayashi S, Hao S, Sakiyama H, Wang X, Yang Q, Akira S, Nishiguchi S, Fujiwara N, et al: Caffeine-stimulated muscle IL-6 mediates alleviation of non-alcoholic fatty liver disease. Biochim Biophys Acta Mol Cell Biol Lipids. 1864:271–280. 2019.PubMed/NCBI View Article : Google Scholar
87	Rollwagen FM, Davis TA, Li YY, Pacheco ND and Zhu XL: Orally administered IL-6 induces elevated intestinal GM-CSF gene expression and splenic CFU-GM. Cytokine. 27:107–112. 2004.PubMed/NCBI View Article : Google Scholar
88	Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L and Karin M: IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 15:103–113. 2009.PubMed/NCBI View Article : Google Scholar
89	Waldner MJ and Neurath MF: Master regulator of intestinal disease: IL-6 in chronic inflammation and cancer development. Semin Immunol. 26:75–79. 2014.PubMed/NCBI View Article : Google Scholar
90	Comen EA, Bowman RL and Kleppe M: Underlying causes and therapeutic targeting of the inflammatory tumor microenvironment. Front Cell Dev Biol. 6(56)2018.PubMed/NCBI View Article : Google Scholar
91	Allen TL, Whitham M and Febbraio MA: IL-6 muscles in on the gut and pancreas to enhance insulin secretion. Cell Metab. 15:8–9. 2012.PubMed/NCBI View Article : Google Scholar
92	Ramis IB, Vianna JS, Gonçalves CV, von Groll A, Dellagostin OA and da Silva PEA: Polymorphisms of the IL-6, IL-8 and IL-10 genes and the risk of gastric pathology in patients infected with Helicobacter pylori. J Microbiol Immunol Infect. 50:153–159. 2017.PubMed/NCBI View Article : Google Scholar
93	Lang Lehrskov L, Lyngbaek MP, Soederlund L, Legaard GE, Ehses JA, Heywood SE, Wewer Albrechtsen NJ, Holst JJ, Karstoft K, Pedersen BK and Ellingsgaard H: Interleukin-6 delays gastric emptying in humans with direct effects on glycemic control. Cell Metab. 27:1201–1211.e3. 2018.PubMed/NCBI View Article : Google Scholar
94	Fan K, Yang C, Fan Z, Huang Q, Zhang Y, Cheng H, Jin K, Lu Y, Wang Z, Luo G, et al: MUC16 C terminal-induced secretion of tumor-derived IL-6 contributes to tumor-associated Treg enrichment in pancreatic cancer. Cancer Lett. 418:167–175. 2018.PubMed/NCBI View Article : Google Scholar
95	Hsieh CL, Liu SJ, Shen CR, Chen MY, Hsu SC, Tsai JP, Li YS, Yang CJ, Chong P and Chen HW: IL-6-transfected tumor cells modulate the status of CD8(+) and CD4(+) T cells to control tumor growth. Immunobiology. 215:486–491. 2010.PubMed/NCBI View Article : Google Scholar
96	Zhang LJ, Liu W, Gao YM, Qin YJ and Wu RD: The expression of IL-6 and STAT3 might predict progression and unfavorable prognosis in Wilms' tumor. Biochem Biophys Res Commun. 435:408–413. 2013.PubMed/NCBI View Article : Google Scholar
97	Wang S, Li L, Zhou Y, He Y, Wei Y and Tao A: Heterotypic cell-in-cell structures in colon cancer can be regulated by IL-6 and lead to tumor immune escape. Exp Cell Res. 382(111447)2019.PubMed/NCBI View Article : Google Scholar
98	Jiang J, Wang GZ, Wang Y, Huang HZ, Li WT and Qu XD: Hypoxia-induced HMGB1 expression of HCC promotes tumor invasiveness and metastasis via regulating macrophage-derived IL-6. Exp Cell Res. 367:81–88. 2018.PubMed/NCBI View Article : Google Scholar
99	Fisher DT, Appenheimer MM and Evans SS: The two faces of IL-6 in the tumor microenvironment. Semin Immunol. 26:38–47. 2014.PubMed/NCBI View Article : Google Scholar
100	Zhao M: Cytokine storm and immunomodulatory therapy in COVID-19: Role of chloroquine and anti-IL-6 monoclonal antibodies. Int J Antimicrob Agents. 55(105982)2020.PubMed/NCBI View Article : Google Scholar
101	Azzi L, Carcano G, Gianfagna F, Grossi P, Gasperina DD, Genoni A, Fasano M, Sessa F, Tettamanti L, Carinci F, et al: Saliva is a reliable tool to detect SARS-CoV-2. J Infect. 81:e45–e50. 2020.PubMed/NCBI View Article : Google Scholar
102	World Health Organization-Coronavirus disease (COVID-2019) situation reports. Available from: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200421-sitrep-92-covid-19.pdf?sfvrsn=38e6b06d_6. Accessed April 23, 2020.
103	Luo P, Liu Y, Qiu L, Liu X, Liu D and Li J: Tocilizumab treatment in COVID-19: A single center experience. J Med Virol. 92:814–818. 2020.PubMed/NCBI View Article : Google Scholar
104	Zhang C, Wu Z, Li JW, Zhao H and Wang GQ: 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. Int J Antimicrob Agents. 55(105954)2020.PubMed/NCBI View Article : Google Scholar
105	Liu B, Li M, Zhou Z, Guan X and Xiang Y: Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 111(102452)2020.PubMed/NCBI View Article : Google Scholar
106	Smolen JS, Aletaha D, Choy EH, Jones SA, Takeuchi T and McInnes I: Targeting IL-6: A review of data. Considerations Med. 2:12–18. 2018.
107	Valle ML, Dworshak J, Sharma A, Ibrahim AS, Al-Shabrawey M and Sharma S: Inhibition of interleukin-6 trans-signaling prevents inflammation and endothelial barrier disruption in retinal endothelial cells. Exp Eye Res. 178:27–36. 2019.PubMed/NCBI View Article : Google Scholar
108	Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van Adelsberg J, Fiore S, Huang X, Yancopoulos GD, Stahl N and Genovese MC: Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: Efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 73:1626–1634. 2014.PubMed/NCBI View Article : Google Scholar
109	Tanaka Y and Mola EM: IL-6 targeting compared to TNF targeting in rheumatoid arthritis: Studies of olokizumab, sarilumab and sirukumab. Ann Rheum Dis. 73:1595–1597. 2014.PubMed/NCBI View Article : Google Scholar
110	Kretsos K, Golor G, Jullion A, Hickling M, McCabe S, Shaw S, Jose J and Oliver R: Safety and pharmacokinetics of olokizumab, an anti-IL-6 monoclonal antibody, administered to healthy male volunteers: A randomized phase I study. Clin Pharmacol Drug Dev. 3:388–395. 2014.PubMed/NCBI View Article : Google Scholar
111	Docea AO, Tsatsakis A, Albulescu D, Cristea O, Zlatian O, Vinceti M, Moschos SA, Tsoukalas D, Goumenou M, Drakoulis N, et al: A new threat from an old enemy: Re-emergence of coronavirus (Review). Int J Mol Med. 45:1631–1643. 2020.PubMed/NCBI View Article : Google Scholar
112	Calina D, Docea AO, Petrakis D, Egorov AM, Ishmukhametov AA, Gabibov AG, Shtilman MI, Kostoff R, Carvalho F, Vinceti M, et al: Towards effective COVID-19 vaccines: Updates, perspectives and challenges (Review). Int J Mol Med. 46:3–16. 2020.PubMed/NCBI View Article : Google Scholar