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Cited by 85Cytokine Signaling Pathways and InteractionsExercise and Physiological ResponsesGenetics, Aging, and Longevity in Model Organisms

The hormetic and hermetic role of IL-6

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Forcina, Laura, Franceschi, Claudio, Musarò, Antonio·2022·Ageing Research Reviews
DOI 10.1016/j.arr.2022.101697
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Abstract

Interleukin-6 is a pleiotropic cytokine regulating different tissues and organs in diverse and sometimes discrepant ways. The dual and sometime hermetic nature of IL-6 action has been highlighted in several contexts and can be explained by the concept of hormesis, in which beneficial or toxic effects can be induced by the same molecule depending on the intensity, persistence, and nature of the stimulation. According with hormesis, a low and/or controlled IL-6 release is associated with anti-inflammatory, antioxidant, and pro-myogenic actions, whereas increased systemic levels of IL-6 can induce pro-inflammatory, pro-oxidant and pro-fibrotic responses. However, many aspects regarding the multifaceted action of IL-6 and the complex nature of its signal transduction remains to be fully elucidated. In this review we collect mechanistic insight into the molecular networks contributing to normal or pathologic changes during advancing age and in chronic diseases. We point out the involvement of IL-6 deregulation in aging-related diseases, dissecting the hormetic action of this key mediator in different tissues, with a special focus on skeletal muscle. Since IL-6 can act as an enhancer of detrimental factor associated with both aging and pathologic conditions, such as chronic inflammation and oxidative stress, this cytokine could represent a "Gerokine", a determinant of the switch from physiologic aging to age-related diseases.

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  • During aging, inflammation, or other pathological conditions, especially in the liver, IL-6 levels are significantly increased and are crucial for the progression of inflammation, fibrosis and carcinogenesis.

    “During aging, inflammation, or other pathological conditions, especially in the liver, IL-6 levels are significantly increased and are crucial for the progression of inflammation, fibrosis and carcinogenesis [1, 2].”

    From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [1]

    Section 4 says IL-6 levels increase with advancing age and in concomitant pathologies. The Introduction says circulating levels rise significantly in diseases associated with inflammation and fibrosis, and describes how IL-6 signaling can sustain inflammation and lead to inflammation-related fibrosis. The paper does not establish that these effects occur especially in the liver or that IL-6 is crucial to carcinogenesis; section 3.1 only hypothesizes a role in sustaining cancer proliferation. (LLM, conf=0.86)

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  1. Adam, N., Rabe, B., Suthaus, J., Grötzinger, J., Rose-John, S., Scheller, J., 2009. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor. J. Virol. 83, 5117-5126. https://doi.org/10.1128/JVI.01601-08. · DOI
  2. Adriaensen, W., Matheï, C., Vaes, B., van Pottelbergh, G., Wallemacq, P., Degryse, J.-M., 2015. Interleukin-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old: a regression and CART approach in the BELFRAIL study. Exp. Gerontol. 69, 53-61. https://doi.org/10.1016/j. exger.2015.06.005. · DOI
  3. Afzali, A.M., Müntefering, T., Wiendl, H., Meuth, S.G., Ruck, T., 2018. Skeletal muscle cells actively shape (auto)immune responses. Autoimmun. Rev. 17, 518-529. https://doi.org/10.1016/J.AUTREV.2017.12.005. · DOI
  4. Akbaraly, T.N., Hamer, M., Ferrie, J.E., Lowe, G., Batty, G.D., Hagger-Johnson, G., Singh- Manoux, A., Shipley, M.J., Kivimäki, M., 2013. Chronic inflammation as a determinant of future aging phenotypes. Can. Med. Assoc. J. 185, E763-E770. https://doi.org/10.1503/cmaj.122072. · DOI
  5. Akira, S., 1997. IL-6-regulated transcription factors. Int. J. Biochem. Cell Biol. 29, 1401-1418. https://doi.org/10.1016/S1357-2725(97)00063-0. · DOI
  6. Alley, D.E., Crimmins, E.M., Karlamangla, A., Hu, P., Seeman, T.E., 2008. Inflammation and rate of cognitive change in high-functioning older adults. J. Gerontol. A. Biol. Sci. Med. Sci. 63, 50-55. https://doi.org/10.1093/GERONA/63.1.50. Aparicio-Siegmund, S., Garbers, Y., Flynn, C.M., Waetzig, G.H., Gouni-Berthold, I., Krone, W., Berthold, H.K., Laudes, M., Rose-John, S., Garbers, C., 2019. The IL-6- neutralizing sIL-6R-sgp130 buffer system is disturbed in patients with type 2 diabetes. Am. J. Physiol. Metab. 317, E411-E420. https://doi.org/10.1152/ ajpendo.00166.2019. · DOI
  7. Barbieri, M., Ferrucci, L., Ragno, E., Corsi, A., Bandinelli, S., Bonafé, M., Olivieri, F., Giovagnetti, S., Franceschi, C., Guralnik, J.M., Paolisso, G., 2003. Chronic inflammation and the effect of IGF-I on muscle strength and power in older persons. Am. J. Physiol. -Endocrinol. Metab. 284. https://doi.org/10.1152/ AJPENDO.00319.2002. · DOI
  8. Beharka, A.A., Meydani, M., Wu, D., Leka, L.S., Meydani, A., Meydani, S.N., 2001. Interleukin-6 production does not increase with age. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 56, B81-B88. https://doi.org/10.1093/gerona/56.2.B81. · DOI · Paper page
  9. Bermejo-Martin, J.F., González-Rivera, M., Almansa, R., Micheloud, D., Tedim, A.P., Domínguez-Gil, M., Resino, S., Martín-Fernández, M., Ryan Murua, P., Pérez- García, F., Tamayo, L., Lopez-Izquierdo, R., Bustamante, E., Aldecoa, C., Gómez, J. M., Rico-Feijoo, J., Orduña, A., Méndez, R., Fernández Natal, I., Megías, G., González-Estecha, M., Carriedo, D., Doncel, C., Jorge, N., Ortega, A., de la Fuente, A., del Campo, F., Fernández-Ratero, J.A., Trapiello, W., González- Jiménez, P., Ruiz, G., Kelvin, A.A., Ostadgavahi, A.T., Oneizat, R., Ruiz, L.M., Miguéns, I., Gargallo, E., Muñoz, I., Pelegrin, S., Martín, S., García Olivares, P., Cedeño, J.A., Ruiz Albi, T., Puertas, C., Berezo, J. Á., Renedo, G., Herrán, R., Bustamante-Munguira, J., Enríquez, P., Cicuendez, R., Blanco, J., Abadia, J., Gómez Barquero, J., Mamolar, N., Blanca-López, N., Valdivia, L.J., Fernández Caso, B., Mantecón, M. Á., Motos, A., Fernandez-Barat, L., Ferrer, R., Barbé, F., Torres, A., Menéndez, R., Eiros, J.M., Kelvin, D.J., 2020. Viral RNA load in plasma is associated with critical illness and a dysregulated host response in COVID-19. Crit. Care 24, 691. https://doi.org/10.1186/s13054-020-03398-0. · DOI
  10. Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T.B., Oukka, M., Weiner, H.L., Kuchroo, V.K., 2006. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235-238. https://doi. org/10.1038/nature04753. · DOI · Paper page
  11. Beyer, I., Njemini, R., Bautmans, I., Demanet, C., Bergmann, P., Mets, T., 2012. Inflammation-related muscle weakness and fatigue in geriatric patients. Exp. Gerontol. 47, 52-59. https://doi.org/10.1016/j.exger.2011.10.005. · DOI
  12. Bihl, M.P., Heinimann, K., Rüdiger, J.J., Eickelberg, O., Perruchoud, A.P., Tamm, M., Roth, M., 2002. Identification of a novel IL-6 isoform binding to the endogenous IL-6 receptor. Am. J. Respir. Cell Mol. Biol. 27, 48-56. https://doi.org/10.1165/ AJRCMB.27.1.4637. · DOI
  13. Bodell, P.W., Kodesh, E., Haddad, F., Zaldivar, F.P., Cooper, D.M., Adams, G.R., 2009. Skeletal muscle growth in young rats is inhibited by chronic exposure to IL-6 but preserved by concurrent voluntary endurance exercise. J. Appl. Physiol. 106, 443-453. https://doi.org/10.1152/JAPPLPHYSIOL.90831.2008/ASSET/IMAGES/ LARGE/ZDG0020983720013.JPEG. · DOI
  14. Bonafè, M., Olivieri, F., Cavallone, L., Giovagnetti, S., Marchegiani, F., Cardelli, M., Pieri, C., Marra, M., Antonicelli, R., Lisa, R., Rizzo, M.R., Paolisso, G., Monti, D., Franceschi, C., 2001. A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur. J. Immunol. 31, 2357-2361. https:// doi.org/10.1002/1521-4141(200108)31:8<2357::AID-IMMU2357>3.0.CO;2-X. · DOI
  15. Bonafè, M., Prattichizzo, F., Giuliani, A., Storci, G., Sabbatinelli, J., Olivieri, F., 2020. Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes. Cytokine Growth Factor Rev. 53, 33-37. https://doi.org/10.1016/j. cytogfr.2020.04.005. · DOI · Paper page
  16. Boulanger, M.J., Chow, D. chone, Brevnova, E.E., Garcia, K.C., 2003. Hexameric structure and assembly of the interieukin-6/IL-6 α-receptor/gp130 complex. Science 300 (80), 2101-2104. https://doi.org/10.1126/SCIENCE.1083901/SUPPL_FILE/ BOULANGER.SOM.PDF. · DOI
  17. Bovijn, J., Lindgren, C.M., Holmes, M.V., 2020. Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19. Lancet Rheumatol. 2, e658-e659. https://doi.org/10.1016/S2665-9913(20)30345-3. · DOI
  18. X. · DOI · Paper page
  19. Campbell, I.L., Abraham, C.R., Masliah, E., Kemper, P., Inglis, J.D., Oldstone, M.B., Mucke, L., 1993. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc. Natl. Acad. Sci. 90, 10061-10065. 〈https://do i.org/10.1073/pnas.90.21.10061〉. · DOI · Paper page
  20. Campbell, I.L., Hofer, M.J., Pagenstecher, A., 2010. Transgenic models for cytokine- induced neurological disease. Biochim. Biophys. Acta Mol. Basis Dis. 1802, 903-917. https://doi.org/10.1016/j.bbadis.2009.10.004. · DOI
  21. Campbell, I.L., Erta, M., Lim, S.L., Frausto, R., May, U., Rose-John, S., Scheller, J., Hidalgo, J., 2014. Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain. J. Neurosci. 34, 2503-2513. https://doi.org/ 10.1523/JNEUROSCI.2830-13.2014. · DOI
  22. Carrivick, S.J., Walsh, J.P., Brown, S.J., Wardrop, R., Hadlow, N.C., 2015. Brief report: does PTH increase with age, independent of 25-hydroxyvitamin D, phosphate, renal function, and ionized calcium? J. Clin. Endocrinol. Metab. 100, 2131-2134. https:// doi.org/10.1210/jc.2014-4370. · DOI
  23. Carson, B.P., 2017. The potential role of contraction-induced myokines in the regulation of metabolic function for the prevention and treatment of type 2 diabetes. Front. Endocrinol. (Lausanne). 8, 97. https://doi.org/10.3389/FENDO.2017.00097/ · DOI
  24. BIBTEX. · DOI
  25. Carson, J.A., Baltgalvis, K.A., 2010. Interleukin 6 as a key regulator of muscle mass during cachexia. Exerc. Sport Sci. Rev. 38, 168-176. https://doi.org/10.1097/ JES.0B013E3181F44F11. · DOI
  26. Chalaris, A., Adam, N., Sina, C., Rosenstiel, P., Lehmann-Koch, J., Schirmacher, P., Hartmann, D., Cichy, J., Gavrilova, O., Schreiber, S., Jostock, T., Matthews, V., Häsler, R., Becker, C., Neurath, M.F., Reiß, K., Saftig, P., Scheller, J., Rose-John, S., 2010. Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice. J. Exp. Med. 207, 1617-1624. https://doi. org/10.1084/jem.20092366. · DOI
  27. Chen, X., Zhao, B., Qu, Y., Chen, Y., Xiong, J., Feng, Y., Men, D., Huang, Q., Liu, Y., Yang, B., Ding, J., Li, F., 2020. Detectable serum severe acute respiratory syndrome coronavirus 2 viral load (RNAemia) is closely correlated with drastically elevated interleukin 6 level in critically Ill patients with coronavirus disease 2019. Clin. Infect. Dis. 71, 1937-1942. https://doi.org/10.1093/cid/ciaa449. · DOI
  28. Christodoulou, C., Cooper, C., 2003. What is osteoporosis? Postgrad. Med. J. 79, 133-138. https://doi.org/10.1136/PMJ.79.929.133. · DOI
  29. Collison, L.W., Delgoffe, G.M., Guy, C.S., Vignali, K.M., Chaturvedi, V., Fairweather, D., Satoskar, A.R., Garcia, K.C., Hunter, C.A., Drake, C.G., Murray, P.J., Vignali, D.A.A., 2012. The composition and signaling of the IL-35 receptor are unconventional. Nat. Immunol. 13, 290-299. https://doi.org/10.1038/ni.2227. · DOI
  30. Conceição, M., Forcina, L., Wiklander, O.P.B., Gupta, D., Nordin, J.Z., Vrellaku, B., McClorey, G., Mäger, I., Gӧrgens, A., Lundin, P., Musarò, A., Wood, M.J.A., Andaloussi, S.E., Roberts, T.C., 2021. Engineered extracellular vesicle decoy receptor-mediated modulation of the IL6 trans-signalling pathway in muscle. Biomaterials 266. https://doi.org/10.1016/j.biomaterials.2020.120435. · DOI
  31. Conte, M., Martucci, M., Mosconi, G., Chiariello, A., Cappuccilli, M., Totti, V., Santoro, A., Franceschi, C., Salvioli, S., 2020. GDF15 plasma level is inversely associated with level of physical activity and correlates with markers of inflammation and muscle weakness. Front. Immunol. 11. https://doi.org/10.3389/ fimmu.2020.00915. · DOI
  32. Conte, M., Giuliani, C., Chiariello, A., Iannuzzi, V., Franceschi, C., Salvioli, S., 2022. GDF15, an emerging key player in human aging. Ageing Res. Rev. 75, 101569 https://doi.org/10.1016/j.arr.2022.101569. · DOI
  33. Coomes, E.A., Haghbayan, H., 2020. Interleukin-6 in Covid-19: a systematic review and meta-analysis. Rev. Med. Virol. 30, 1-9. https://doi.org/10.1002/rmv.2141. · DOI
  34. Cortez-Cooper, M., Meaders, E., Stallings, J., Haddow, S., Kraj, B., Sloan, G., McCully, K. K., Cannon, J.G., 2013. Soluble TNF and IL-6 receptors: indicators of vascular health in women without cardiovascular disease. Vasc. Med. 18, 282-289. https://doi.org/ 10.1177/1358863X13508336. · DOI
  35. Costa-Pereira, A.P., Tininini, S., Strobl, B., Alonzi, T., Schlaak, J.F., Is'harc, H., Gesualdo, I., Newman, S.J., Kerr, I.M., Poli, V., 2002. Mutational switch of an IL-6 response to an interferon-γ-like response. Proc. Natl. Acad. Sci. 99, 8043-8047. 〈https://doi. org/10.1073/pnas.122236099〉. · DOI
  36. Cronjé, H.T., Nienaber-Rousseau, C., Zandberg, L., de Lange, Z., Green, F.R., Pieters, M., 2017. Fibrinogen and clot-related phenotypes determined by fibrinogen polymorphisms: independent and IL-6-interactive associations. PLoS One 12, e0187712. https://doi.org/10.1371/journal.pone.0187712. · DOI
  37. Dastan, F., Saffaei, A., Haseli, S., Marjani, M., Moniri, A., Abtahian, Z., Abedini, A., Kiani, A., Seifi, S., Jammati, H., Hashemian, S.M.R., Pourabdollah Toutkaboni, M., Eslaminejad, A., Heshmatnia, J., Sadeghi, M., Nadji, S.A., Dastan, A., Baghaei, P., Varahram, M., Yousefian, S., Salamzadeh, J., Tabarsi, P., 2020. Promising effects of tocilizumab in COVID-19: a non-controlled, prospective clinical trial. Int. Immunopharmacol. 88, 106869 https://doi.org/10.1016/j.intimp.2020.106869. · DOI
  38. Davalli, P., Mitic, T., Caporali, A., Lauriola, A., D'Arca, D., 2016. ROS, cell senescence, and novel molecular mechanisms in aging and age-related diseases. Oxid. Med. Cell. Longev. 2016, 1-18. https://doi.org/10.1155/2016/3565127. · DOI · Paper page
  39. Davalos, D., Akassoglou, K., 2012. Fibrinogen as a key regulator of inflammation in disease. Semin. Immunopathol. 34, 43-62. https://doi.org/10.1007/S00281-011- 0290-8. · DOI
  40. De Benedetti, F., Rucci, N., Del Fattore, A., Peruzzi, B., Paro, R., Longo, M., Vivarelli, M., Muratori, F., Berni, S., Ballanti, P., Ferrari, S., Teti, A., 2006. Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis Rheum. 54, 3551-3563. https://doi.org/10.1002/ART.22175. · DOI
  41. Di Bona, D., Vasto, S., Capurso, C., Christiansen, L., Deiana, L., Franceschi, C., Hurme, M., Mocchegiani, E., Rea, M., Lio, D., Candore, G., Caruso, C., 2009. Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta- analysis. Ageing Res. Rev. 8, 36-42. https://doi.org/10.1016/J.ARR.2008.09.001. · DOI
  42. Diehl, S., Rincón, M., 2002. The two faces of IL-6 on Th1/Th2 differentiation. Mol. Immunol. 39, 531-536. https://doi.org/10.1016/S0161-5890(02)00210-9. · DOI
  43. Dienz, O., Rud, J.G., Eaton, S.M., Lanthier, P.A., Burg, E., Drew, A., Bunn, J., Suratt, B.T., Haynes, L., Rincon, M., 2012. Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung. Mucosal Immunol. 5, 258-266. https://doi.org/10.1038/mi.2012. · DOI
  44. Dittrich, E., Rose-John, S., Gerhartz, C., Müllberg, J., Stoyan, T., Yasukawa, K., Heinrich, P.C., Graeve, L., 1994. Identification of a region within the cytoplasmic domain of the interleukin-6 (IL-6) signal transducer gp130 important for ligand- induced endocytosis of the IL-6 receptor. J. Biol. Chem. 269, 19014-19020. https:// doi.org/10.1016/S0021-9258(17)32267-6. · DOI
  45. Doumanov, J.A., Daubrawa, M., Unden, H., Graeve, L., 2006. Identification of a basolateral sorting signal within the cytoplasmic domain of the interleukin-6 signal transducer gp130. Cell. Signal. 18, 1140-1146. https://doi.org/10.1016/j. cellsig.2005.09.006. · DOI
  46. Eberhardt, K.A., Meyer-Schwickerath, C., Heger, E., Knops, E., Lehmann, C., Rybniker, J., Schommers, P., Eichenauer, D.A., Kurth, F., Ramharter, M., Kaiser, R., Holtick, U., Klein, F., Jung, N., Di Cristanziano, V., 2020. RNAemia corresponds to disease severity and antibody response in hospitalized COVID-19 patients. Viruses 12, 1045. https://doi.org/10.3390/v12091045. · DOI
  47. Ebisui, C., Tsujinaka, T., Morimoto, T., Kan, K., Iijima, S., Yano, M., Kominami, E., Tanaka, K., Monden, M., 1995. Interleukin-6 induces proteolysis by activating intracellular proteases (Cathepsins B and L, Proteasome) in C2C12 myotubes. Clin. Sci. 89, 431-439. https://doi.org/10.1042/cs0890431. · DOI
  48. Eljilany, I., Elzouki, A.-N., 2020. D-dimer, fibrinogen, and IL-6 in COVID-19 patients with suspected venous thromboembolism: a narrative review. Vasc. Health Risk Manag Volume 16, 455-462. https://doi.org/10.2147/VHRM.S280962. · DOI
  49. Elosua, R., Bartali, B., Ordovas, J.M., Corsi, A.M., Lauretani, F., Ferrucci, L., 2005. Association between physical activity, physical performance, and inflammatory biomarkers in an elderly population: the InCHIANTI study. J. Gerontol. A. Biol. Sci. Med. Sci. 60, 760-767. https://doi.org/10.1093/GERONA/60.6.760. · DOI · Paper page
  50. Ershler, W.B., 1993. Interleukin-6: a cytokine for gerontolgists. J. Am. Geriatr. Soc. 41, 176-181. https://doi.org/10.1111/j.1532-5415.1993.tb02054.x. · DOI
  51. Fajar, J.K., Azharuddin, A., 2017. The association between interleukin 6 -174 G/C gene polymorphism and the risk of osteoporosis: a meta-analysis. J. Taibah Univ. Med. Sci. 12, 212-220. https://doi.org/10.1016/J.JTUMED.2016.07.010. · DOI
  52. Fattori, E., Lazzaro, D., Musiani, P., Modesti, A., Alonzi, T., Ciliberto, G., 1995. IL-6 expression in neurons of transgenic mice causes reactive astrocytosis and increase in ramified microglial cells but no neuronal damage. Eur. J. Neurosci. 7, 2441-2449. https://doi.org/10.1111/j.1460-9568.1995.tb01042.x. · DOI
  53. Ferrando-Martínez, S., Romero-Sánchez, M.C., Solana, R., Delgado, J., de la Rosa, R., Muñoz-Fernández, M. Á., Ruiz-Mateos, E., Leal, M., 2013. Thymic function failure and C-reactive protein levels are independent predictors of all-cause mortality in healthy elderly humans. Age 35, 251-259. https://doi.org/10.1007/s11357-011- 9341-2. · DOI
  54. Ferrucci, L., Corsi, A., Lauretani, F., Bandinelli, S., Bartali, B., Taub, D.D., Guralnik, J.M., Longo, D.L., 2005. The origins of age-related proinflammatory state. Blood 105, 2294-2299. https://doi.org/10.1182/blood-2004-07-2599. · DOI · Paper page
  55. Filgueiras-Rama, D., Rivera Torres, J., Andrés, V., 2018. Electrocardiographic abnormalities in patients with hutchinson-gilford progeria syndrome. JAMA Cardiol. 3, 1024. https://doi.org/10.1001/jamacardio.2018.2100. · DOI
  56. Fishman, D., Faulds, G., Jeffey, R., Mohamed-Ali, V., Yudkin, J.S., Humphries, S., Woo, P., 1998. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J. Clin. Invest. 102, 1369-1376. https://doi.org/10.1172/ JCI2629. · DOI · Paper page
  57. Flynn, C.M., Kespohl, B., Daunke, T., Garbers, Y., Düsterhöft, S., Rose-John, S., Haybaeck, J., Lokau, J., Aparicio-Siegmund, S., Garbers, C., 2021. Interleukin-6 controls recycling and degradation, but not internalization of its receptors. J. Biol. Chem. 296, 100434 https://doi.org/10.1016/j.jbc.2021.100434. · DOI
  58. Forcina, L., Miano, C., Musarò, A., 2018. The physiopathologic interplay between stem cells and tissue niche in muscle regeneration and the role of IL-6 on muscle homeostasis and diseases. Cytokine Growth Factor Rev. https://doi.org/10.1016/j. cytogfr.2018.05.001. · DOI
  59. Forcina, L., Miano, C., Pelosi, L., Musarò, A., 2019a. An overview about the biology of skeletal muscle satellite cells. Curr. Genom. 20 https://doi.org/10.2174/ 1389202920666190116094736. · DOI
  60. Forcina, L., Miano, C., Scicchitano, B., Musarò, A., 2019b. Signals from the niche: insights into the role of IGF-1 and IL-6 in modulating skeletal muscle fibrosis. Cells 8, 232. https://doi.org/10.3390/cells8030232. · DOI
  61. Forcina, L., Miano, C., Scicchitano, B.M., Rizzuto, E., Berardinelli, M.G., De Benedetti, F., Pelosi, L., Musarò, A., 2019c. Increased Circulating Levels of Interleukin-6 Affect the Redox Balance in Skeletal Muscle. Oxid. Med. Cell. Longev. 2019 https://doi.org/ 10.1155/2019/3018584. · DOI
  62. Franchimont, N., Wertz, S., Malaise, M., 2005. Interleukin-6: an osteotropic factor influencing bone formation? Bone 37, 601-606. https://doi.org/10.1016/J. BONE.2005.06.002. · DOI
  63. Fujimoto, K., Ida, H., Hirota, Y., Ishigai, M., Amano, J., Tanaka, Y., 2015. Intracellular dynamics and fate of a humanized anti-interleukin-6 receptor monoclonal antibody, Tocilizumab. Mol. Pharmacol. 88, 660-675. https://doi.org/10.1124/ mol.115.099184. · DOI
  64. Fuster, J.J., Walsh, K., 2014. The good, the bad, and the ugly of interleukin-6 signaling. EMBO J. 33, 1425-1427. https://doi.org/10.15252/embj.201488856. · DOI
  65. Gabay, C., 2006. Interleukin-6 and chronic inflammation. Arthritis Res. Ther. 8 Suppl 2, S3. https://doi.org/10.1186/ar1917. · DOI
  66. Garbers, C., Monhasery, N., Aparicio-Siegmund, S., Lokau, J., Baran, P., Nowell, M.A., Jones, S.A., Rose-John, S., Scheller, J., 2014. The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases. Biochim. Biophys. Acta -Mol. Basis Dis. 1842, 1485-1494. https://doi.org/10.1016/j.bbadis.2014.05.018. · DOI · Paper page
  67. Garbers, C., Heink, S., Korn, T., Rose-John, S., 2018. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat. Rev. Drug Discov. 17, 395-412. https:// doi.org/10.1038/nrd.2018. · DOI · Paper page
  68. Giacconi, R., Cipriano, C., Albanese, F., Boccoli, G., Saba, V., Olivieri, F., Franceschi, C., Mocchegiani, E., 2004. The -174G/C polymorphism of IL-6 is useful to screen old subjects at risk for atherosclerosis or to reach successful ageing. Exp. Gerontol. 39, 621-628. https://doi.org/10.1016/j.exger.2003.12.013. · DOI
  69. X. · DOI · Paper page
  70. Godbout, J.P., Johnson, R.W., 2004. Interleukin-6 in the aging brain. J. Neuroimmunol. 147, 141-144. https://doi.org/10.1016/J.JNEUROIM.2003.10.031. · DOI
  71. Gonzalo, S., Kreienkamp, R., Askjaer, P., 2017. Hutchinson-gilford progeria syndrome: a premature aging disease caused by LMNA gene mutations. Ageing Res. Rev. 33, 18-29. https://doi.org/10.1016/j.arr.2016.06.007. · DOI · Paper page
  72. Gritti, G., Raimondi, F., Bottazzi, B., Ripamonti, D., Riva, I., Landi, F., Alborghetti, L., Frigeni, M., Damiani, M., Micò, C., Fagiuoli, S., Lorini, F.L., Gandini, L., Novelli, L., Morgan, J.P., Owens, B.M.J., Kanhai, K.J.K., Reljanovic, G.T., Rizzi, M., Di Marco, F., Mantovani, A., Rambaldi, A., 2021. Siltuximab downregulates interleukin-8 and pentraxin 3 to improve ventilatory status and survival in severe COVID-19. Leukemia 35, 2710-2714. https://doi.org/10.1038/s41375-021-01299-x. · DOI
  73. Guaraldi, G., Meschiari, M., Cozzi-Lepri, A., Milic, J., Tonelli, R., Menozzi, M., Franceschini, E., Cuomo, G., Orlando, G., Borghi, V., Santoro, A., Di Gaetano, M., Puzzolante, C., Carli, F., Bedini, A., Corradi, L., Fantini, R., Castaniere, I., Tabbì, L., Girardis, M., Tedeschi, S., Giannella, M., Bartoletti, M., Pascale, R., Dolci, G., Brugioni, L., Pietrangelo, A., Cossarizza, A., Pea, F., Clini, E., Salvarani, C., Massari, M., Viale, P.L., Mussini, C., 2020. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheuma 2, e474-e484. https://doi. org/10.1016/S2665-9913(20)30173-9. · DOI · Paper page
  74. Gubernatorova, E.O., Gorshkova, E.A., Polinova, A.I., Drutskaya, M.S., 2020. IL-6: relevance for immunopathology of SARS-CoV-2. Cytokine Growth Factor Rev. 53, 13-24. https://doi.org/10.1016/j.cytogfr.2020.05.009. · DOI
  75. Gyengesi, E., Rangel, A., Ullah, F., Liang, H., Niedermayer, G., Asgarov, R., Venigalla, M., Gunawardena, D., Karl, T., Münch, G., 2019. Chronic microglial activation in the GFAP-IL6 mouse contributes to age-dependent cerebellar volume loss and impairment in motor function. Front. Neurosci. 13, 303. https://doi.org/10.3389/ FNINS.2019.00303/BIBTEX. · DOI
  76. Hamczyk, M.R., del Campo, L., Andrés, V., 2018. Aging in the cardiovascular system: lessons from hutchinson-gilford progeria syndrome. Annu. Rev. Physiol. 80, 27-48. https://doi.org/10.1146/annurev-physiol-021317-121454. · DOI
  77. Harris, T.B., Ferrucci, L., Tracy, R.P., Corti, M.C., Wacholder, S., Ettinger, W.H., Heimovitz, H., Cohen, H.J., Wallace, R., 1999. Associations of elevated Interleukin-6 and C-Reactive protein levels with mortality in the elderly**Access the "Journal Club" discussion of this paper at http:/www.elsevier.com/locate/ajmselect/. Am. J. Med. 106, 506-512. 〈https://doi.org/10.1016/S0002-9343(99)00066-2〉. · DOI · Paper page
  78. He, B., Yin, X., Hao, D., Zhang, X., Zhang, Z., Zhang, K., Yang, X., 2020. Blockade of IL-6 alleviates bone loss induced by modelled microgravity in mice. Can. J. Physiol. Pharmacol. 98, 678-683. https://doi.org/10.1139/CJPP-2019-0632/SUPPL_FILE/ CJPP-2019-0632SUPPLA.DOCX. · DOI
  79. Heink, S., Yogev, N., Garbers, C., Herwerth, M., Aly, L., Gasperi, C., Husterer, V., Croxford, A.L., Möller-Hackbarth, K., Bartsch, H.S., Sotlar, K., Krebs, S., Regen, T., Blum, H., Hemmer, B., Misgeld, T., Wunderlich, T.F., Hidalgo, J., Oukka, M., Rose- John, S., Schmidt-Supprian, M., Waisman, A., Korn, T., 2017. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat. Immunol. 18, 74-85. https://doi.org/10.1038/ni.3632. · DOI
  80. Heinrich, P.C., Castell, J.V., Andus, T., 1990. Interleukin-6 and the acute phase response. Biochem. J. 265, 621-636. https://doi.org/10.1042/bj2650621. · DOI · Paper page
  81. Hershko, D.D., Robb, B.W., Luo, G., Hasselgren, P.O., 2002. Multiple transcription factors regulating the IL-6 gene are activated by cAMP in cultured Caco-2 cells. Am. J. Physiol. Regul. Integr. Comp. Physiol. 283, 1140-1148. https://doi.org/10.1152/ AJPREGU.00161.2002/ASSET/IMAGES/LARGE/H61121439008.JPEG. · DOI
  82. Hetzler, K.L., Hardee, J.P., Puppa, M.J., Narsale, A.A., Sato, S., Davis, J.M., Carson, J.A., 2015. Sex differences in the relationship of IL-6 signaling to cancer cachexia progression. Biochim. Biophys. Acta Mol. Basis Dis. 1852, 816-825. https://doi.org/ 10.1016/j.bbadis.2014.12.015. · DOI
  83. Heymann, D., Rousselle, A.V., 2000. gp130 cytokine family and bone cells. Cytokine 12, 1455-1468. https://doi.org/10.1006/CYTO.2000.0747. · DOI
  84. Hirahara, K., Onodera, A., Villarino, A.V., Bonelli, M., Sciumè, G., Laurence, A., Sun, H.- W., Brooks, S.R., Vahedi, G., Shih, H.-Y., Gutierrez-Cruz, G., Iwata, S., Suzuki, R., Mikami, Y., Okamoto, Y., Nakayama, T., Holland, S.M., Hunter, C.A., Kanno, Y., O'Shea, J.J., 2015. Asymmetric action of STAT transcription factors drives transcriptional outputs and cytokine specificity. Immunity 42, 877-889. https://doi. org/10.1016/j.immuni.2015.04.014. · DOI
  85. Hoffmann, S.C., Stanley, E.M., Darrin Cox, E., Craighead, N., DiMercurio, B.S., Koziol, D. E., Harlan, D.M., Kirk, A.D., Blair, P.J., 2001. Association of cytokine polymorphic inheritance and in vitro cytokine production in Anti-CD3/CD28-stimulated peripheral blood lymphocytes1. Transplantation 72, 1444-1450. https://doi.org/ 10.1097/00007890-200110270-00019. · DOI
  86. Hoischen, S.H., Vollmer, P., März, P., Özbek, S., Götze, K.S., Peschel, C., Jostock, T., Geib, T., Müllberg, J., Mechtersheimer, S., Fischer, M., Grötzinger, J., Galle, P.R., Rose-John, S., 2000. Human herpes virus 8 interleukin-6 homologue triggers gp130 on neuronal and hematopoietic cells. Eur. J. Biochem 267, 3604-3612. https://doi. org/10.1046/J.1432-1327.2000.01389.X. · DOI
  87. Jenny, N.S., French, B., Arnold, A.M., Strotmeyer, E.S., Cushman, M., Chaves, P.H.M., Ding, J., Fried, L.P., Kritchevsky, S.B., Rifkin, D.E., Sarnak, M.J., Newman, A.B., 2012. Long-term assessment of inflammation and healthy aging in late life: the cardiovascular health study all stars. J. Gerontol. Ser. A 67, 970-976. https://doi. org/10.1093/gerona/glr261. · DOI
  88. Jones, S.A., Hunter, C.A., 2021. Is IL-6 a key cytokine target for therapy in COVID-19? Nat. Rev. Immunol. 21, 337-339. https://doi.org/10.1038/s41577-021-00553-8. · DOI
  89. Jones, S.A., Horiuchi, S., Topley, N., Yamamoto, N., Fuller, G.M., 2001. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J. 15, 43-58. https://doi.org/10.1096/fj.99-1003rev. · DOI
  90. Jostock, T., Müllberg, J., Özbek, S., Atreya, R., Blinn, G., Voltz, N., Fischer, M., Neurath, M.F., Rose-John, S., 2001. Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur. J. Biochem 268, 160-167. https://doi.org/10.1046/j.1432-1327.2001.01867.x. · DOI
  91. Jylha, M., Paavilainen, P., Lehtimaki, T., Goebeler, S., Karhunen, P.J., Hervonen, A., Hurme, M., 2007. Interleukin-1 receptor antagonist, interleukin-6, and C-reactive protein as predictors of mortality in nonagenarians: the vitality 90+ study. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 62, 1016-1021. https://doi.org/10.1093/ gerona/62.9.1016. · DOI
  92. Kemna, E., Pickkers, P., Nemeth, E., Van Der Hoeven, H., Swinkels, D., 2005. Time- course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 106, 1864-1866. https://doi.org/10.1182/BLOOD-2005- 03-1159. · DOI · Paper page
  93. Kennedy, S.A., Baerlocher, M.O., Baerlocher, F., Socko, D., Sacks, D., Nikolic, B., Wojak, J.C., Haskal, Z.J., 2016. Meta-analysis of local endovascular therapy for acute ischemic stroke. J. Vasc. Interv. Radiol. 27, 307-321. https://doi.org/ 10.1016/j.jvir.2015.11.053. · DOI
  94. Kimura, A., Naka, T., Kishimoto, T., 2007. IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proc. Natl. Acad. Sci. 104, 12099-12104. 〈https://doi.org/10.1073/pnas.0705268104〉. · DOI
  95. Kokje, V.B.C., Gäbel, G., Koole, D., Northoff, B.H., Holdt, L.M., Hamming, J.F., Lindeman, J.H.N., 2016. IL-6: a Janus-like factor in abdominal aortic aneurysm disease. Atherosclerosis 251, 139-146. https://doi.org/10.1016/j. atherosclerosis.2016.06.021. · DOI
  96. Korn, T., Hiltensperger, M., 2021. Role of IL-6 in the commitment of T cell subsets. Cytokine 146, 155654. https://doi.org/10.1016/j.cyto.2021.155654. · DOI
  97. Kudo, O., Sabokbar, A., Pocock, A., Itonaga, I., Fujikawa, Y., Athanasou, N., 2003. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL- independent mechanism. Bone 32, 1-7. https://doi.org/10.1016/S8756-3282(02) 00915-8. · DOI
  98. Kwak, K.S., Zhou, X., Solomon, V., Baracos, V.E., Davis, J., Bannon, A.W., Boyle, W.J., Lacey, D.L., Han, H.Q., 2004. Regulation of protein catabolism by muscle-specific and cytokine-inducible ubiquitin ligase E3alpha-II during cancer cachexia. Cancer Res 64, 8193-8198. https://doi.org/10.1158/0008-5472.CAN-04-2102. · DOI
  99. Lee, J.H., Jun, H.S., 2019. Role of myokines in regulating skeletal muscle mass and function. Front. Physiol. 10, 42. https://doi.org/10.3389/FPHYS.2019.00042/ · DOI
  100. BIBTEX. · DOI
  101. Lee, J.-Y., Hall, J.A., Kroehling, L., Wu, L., Najar, T., Nguyen, H.H., Lin, W.-Y., Yeung, S. T., Silva, H.M., Li, D., Hine, A., Loke, P., Hudesman, D., Martin, J.C., Kenigsberg, E., Merad, M., Khanna, K.M., Littman, D.R., 2020. Serum amyloid A proteins induce pathogenic Th17 cells and promote inflammatory disease. Cell 183, 2036-2039. https://doi.org/10.1016/j.cell.2020.12.008. · DOI
  102. Li, X., Yang, T., Sun, Z., 2019. Hormesis in Health and Chronic Diseases. Trends Endocrinol. Metab. 30, 944-958. https://doi.org/10.1016/j.tem.2019.08.007. · DOI
  103. Li, Y., Lu, L., Xie, Y., Chen, X., Tian, L., Liang, Y., Li, H., Zhang, J., Liu, Y., Yu, X., 2021. Interleukin-6 knockout inhibits senescence of bone mesenchymal stem cells in high- fat diet-induced bone loss. Front. Endocrinol. (Lausanne) 11. https://doi.org/ 10.3389/fendo.2020.622950. · DOI
  104. Lin, T., Liu, G.A., Perez, E., Rainer, R.D., Febo, M., Cruz-Almeida, Y., Ebner, N.C., 2018. Systemic inflammation mediates age-related cognitive deficits. Front. Aging Neurosci. 10 https://doi.org/10.3389/fnagi.2018.00236. · DOI · Paper page
  105. Linton, P.J., Dorshkind, K., 2004. Age-related changes in lymphocyte development and function. Nat. Immunol. 5, 133-139. https://doi.org/10.1038/ni1033. · DOI
  106. Liu, H., Huang, Y., Lyu, Y., Dai, W., Tong, Y., Li, Y., 2021. GDF15 as a biomarker of ageing. Exp. Gerontol. 146, 111228 https://doi.org/10.1016/j.exger.2021.111228. · DOI
  107. Luo, Y., Zheng, S.G., 2016. Hall of fame among pro-inflammatory cytokines: Interleukin- 6 gene and its transcriptional regulation mechanisms. Front. Immunol. 7, 604. https://doi.org/10.3389/FIMMU.2016.00604/BIBTEX. · DOI
  108. Martens, A.S., Bode, J.G., Heinrich, P.C., Graeve, L., 2000. The cytoplasmic domain of the interleukin-6 receptor gp80 mediates its basolateral sorting in polarized madin- darby canine kidney cells. J. Cell Sci. 113, 3593-3602. https://doi.org/10.1242/ jcs.113.20.3593. · DOI
  109. Martin, K.R., Barrett, J.C., 2002. Reactive oxygen species as double-edged swords in cellular processes: low-dose cell signaling versus high-dose toxicity. Hum. Exp. Toxicol. 21, 71-75. https://doi.org/10.1191/0960327102ht213oa. · DOI
  110. Martucci, M., Ostan, R., Biondi, F., Bellavista, E., Fabbri, C., Bertarelli, C., Salvioli, S., Capri, M., Franceschi, C., Santoro, A., 2017. Mediterranean diet and inflammaging within the hormesis paradigm. Nutr. Rev. 75, 442-455. https://doi.org/10.1093/ NUTRIT/NUX013. · DOI
  111. Martucci, M., Conte, M., Ostan, R., Chiariello, A., Miele, F., Franceschi, C., Salvioli, S., Santoro, A., Provini, F., 2020. Both objective and paradoxical insomnia elicit a stress response involving mitokine production. Aging 12, 10497-10505. https://doi.org/ 10.18632/aging.103274. · DOI
  112. Mauer, J., Chaurasia, B., Goldau, J., Vogt, M.C., Ruud, J., Nguyen, K.D., Theurich, S., Hausen, A.C., Schmitz, J., Brönneke, H.S., Estevez, E., Allen, T.L., Mesaros, A., Partridge, L., Febbraio, M.A., Chawla, A., Wunderlich, F.T., Brüning, J.C., 2014. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 15, 423-430. https://doi.org/10.1038/ni.2865. · DOI · Paper page
  113. Mauer, J., Denson, J.L., Brüning, J.C., 2015. Versatile functions for IL-6 in metabolism and cancer. Trends Immunol. 36, 92-101. https://doi.org/10.1016/j.it.2014.12.008. · DOI
  114. Maurel, S., Hamon, B., Taillandier, J., Rudant, E., Bonhomme-Faivre, L., Trivalle, C., 2007. Prognostic value of serum interleukin-6 (IL-6) levels in long term care. Arch. Gerontol. Geriatr. 45, 65-71. https://doi.org/10.1016/j.archger.2006.09.003. · DOI
  115. Mihara, M., Hashizume, M., Yoshida, H., Suzuki, M., Shiina, M., 2012. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin. Sci. 122, 143-159. https://doi.org/10.1042/CS20110340. · DOI
  116. Mikó, A., Pótó, L., Mátrai, P., Hegyi, P., Füredi, N., Garami, A., Illés, A., Solymár, M., Vincze, Á., Balaskó, M., Pár, G., Sarlós, P., Bajor, J., Tenk, J., Rostás, I., Pétervári, E., 2018. Gender difference in the effects of interleukin-6 on grip strength -a systematic review and meta-analysis. BMC Geriatr. 18, 107. https://doi.org/10.1186/s12877- 018-0798-z. · DOI
  117. Miller, P.D., Hattersley, G., Riis, B.J., Williams, G.C., Lau, E., Russo, L.A., Alexandersen, P., Zerbini, C.A.F., Hu, M., Harris, A.G., Fitzpatrick, L.A., Cosman, F., Christiansen, C., 2016. Effect of abaloparatide vs placebo on new vertebral fractures in postmenopausal women with osteoporosis. JAMA 316, 722. https://doi.org/ 10.1001/jama.2016.11136. · DOI
  118. Minciullo, P.L., Catalano, A., Mandraffino, G., Casciaro, M., Crucitti, A., Maltese, G., Morabito, N., Lasco, A., Gangemi, S., Basile, G., 2016. Inflammaging and anti- inflammaging: the role of cytokines in extreme longevity. Arch. Immunol. Ther. Exp. 64, 111-126. https://doi.org/10.1007/s00005-015-0377-3. · DOI · Paper page
  119. Mocco, J., Zaidat, O.O., von Kummer, R., Yoo, A.J., Gupta, R., Lopes, D., Frei, D., Shownkeen, H., Budzik, R., Ajani, Z.A., Grossman, A., Altschul, D., McDougall, C., Blake, L., Fitzsimmons, B.-F., Yavagal, D., Terry, J., Farkas, J., Lee, S.K., Baxter, B., Wiesmann, M., Knauth, M., Heck, D., Hussain, S., Chiu, D., Alexander, M.J., Malisch, T., Kirmani, J., Miskolczi, L., Khatri, P., 2016. Aspiration thrombectomy after intravenous alteplase versus intravenous alteplase alone. Stroke 47, 2331-2338. https://doi.org/10.1161/STROKEAHA.116.013372. · DOI
  120. Muñoz-Cánoves, P., Scheele, C., Pedersen, B.K., Serrano, A.L., 2013. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J. 280, 4131-4148. https://doi.org/10.1111/febs.12338. · DOI · Paper page
  121. Murthy, L., Duque, G., 2021. Parathyroid hormone levels and aging: Effect on balance. pp. 173-184. 〈https://doi.org/10.1016/bs.vh.2020.12.009〉. · DOI
  122. Narazaki, M., Yasukawa, K., Saito, T., Ohsugi, Y., Fukui, H., Koishihara, Y., Yancopoulos, G.D., Taga, T., Kishimoto, T., 1993. Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood 82, 1120-1126. https://doi.org/10.1182/BLOOD.V82.4.1120.1120. · DOI
  123. Neipel, F., Albrecht, J.-C., Ensser, A., Huang, Y.-Q., Li, J.J., Friedman-Kien, A.E., Fleckenstein, B., 1997. Human herpesvirus 8 encodes a homolog of interleukin-6. J. Virol. 71, 839-842. https://doi.org/10.1128/JVI.71.1.839-842.1997. · DOI
  124. Nolte, A.A., Movin, M., Lundin, H., Salminen, H., 2015. IGFBP-1 predicts all-cause mortality in elderly women independently of IGF-I. Growth Horm. IGF Res 25, 281-285. https://doi.org/10.1016/j.ghir.2015.09.001. · DOI
  125. Novick, D., Engelmann, H., Wallach, D., Rubinstein, M., 1989. Soluble cytokine receptors are present in normal human urine. J. Exp. Med. 170, 1409-1414. https://doi.org/ 10.1084/JEM.170.4.1409. · DOI
  126. Olivieri, F., Bonafè, M., Cavallone, L., Giovagnetti, S., Marchegiani, F., Cardelli, M., Mugianesi, E., Giampieri, C., Moresi, R., Stecconi, R., Lisa, R., Franceschi, C., 2002. The -174C/G locus affects in vitro/in vivo IL-6 production during aging. Exp. Gerontol. 37, 309-314. https://doi.org/10.1016/S0531-5565(01)00197-8. · DOI
  127. Patterson, C.C., Smith, A.E., Yarnell, J.W.G., Rumley, A., Ben-Shlomo, Y., Lowe, G.D.O., 2010. The associations of interleukin-6 (IL-6) and downstream inflammatory markers with risk of cardiovascular disease: the Caerphilly study. Atherosclerosis 209, 551-557. https://doi.org/10.1016/j.atherosclerosis.2009.09.030. · DOI
  128. X. · DOI · Paper page
  129. Pedersen, B.K., Steensberg, A., Schjerling, P., 2001. Muscle-derived interleukin-6: possible biological effects. J. Physiol. 536, 329-337. https://doi.org/10.1111/ j.1469-7793.2001.0329c.xd. · DOI · Paper page
  130. Pelosi, L., Berardinelli, M.G., Forcina, L., Spelta, E., Rizzuto, E., Nicoletti, C., Camilli, C., Testa, E., Catizone, A., De Benedetti, F., Musarò, A., 2015. Increased levels of interleukin-6 exacerbate the dystrophic phenotype in mdx mice. Hum. Mol. Genet 24. https://doi.org/10.1093/hmg/ddv323. · DOI
  131. Pelosi, L., Forcina, L., Nicoletti, C., Scicchitano, B.M., Musarò, A., 2017. Increased circulating levels of interleukin-6 induce perturbation in redox-regulated signaling cascades in muscle of dystrophic mice. Oxid. Med. Cell. Longev. 2017 https://doi. org/10.1155/2017/1987218. · DOI
  132. Pelosi, L., Berardinelli, M.G., Forcina, L., Ascenzi, F., Rizzuto, E., Sandri, M., De Benedetti, F., Scicchitano, B.M., Musarò, A., 2021. Sustained systemic levels of IL-6 impinge early muscle growth and induce muscle atrophy and wasting in adulthood. Cells 10. https://doi.org/10.3390/CELLS10071816. · DOI
  133. Pelosi, M., De Rossi, M., Barberi, L., Musarò, A., 2014. IL-6 impairs myogenic differentiation by downmodulation of p90RSK/eEF2 and mTOR/p70S6K axes, without affecting AKT activity. Biomed. Res. Int. 2014, 206026 https://doi.org/ 10.1155/2014/206026. · DOI
  134. Perry, V.H., Newman, T.A., Cunningham, C., 2003. The impact of systemic infection on the progression of neurodegenerative disease. Nat. Rev. Neurosci. 4, 103-112. https://doi.org/10.1038/nrn1032. · DOI · Paper page
  135. Petrillo, S., Pelosi, L., Piemonte, F., Travaglini, L., Forcina, L., Catteruccia, M., Petrini, S., Verardo, M., D'Amico, A., Musaró, A., Bertini, E., 2017. Oxidative stress in Duchenne muscular DYSTROPHY: focus on the NRF2 redox pathway. Hum. Mol. Genet. 26 https://doi.org/10.1093/hmg/ddx173. · DOI
  136. Petruzzelli, M., Schweiger, M., Schreiber, R., Campos-Olivas, R., Tsoli, M., Allen, J., Swarbrick, M., Rose-John, S., Rincon, M., Robertson, G., Zechner, R., Wagner, E.F., 2014. A switch from white to brown fat increases energy expenditure in cancer- associated cachexia. Cell Metab. 20, 433-447. https://doi.org/10.1016/j. cmet.2014.06.011. · DOI
  137. Poli, V., Balena, R., Fattori, E., Markatos, A., Yamamoto, M., Tanaka, H., Ciliberto, G., Rodan, G.A., Costantini, F., 1994. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J. 13, 1189-1196. https://doi.org/ 10.1002/j.1460-2075.1994.tb06368.x. · DOI
  138. Poljsak, B., Šuput, D., Milisav, I., 2013. Achieving the balance between ROS and antioxidants: when to use the synthetic antioxidants. Oxid. Med. Cell. Longev. 2013, 1-11. https://doi.org/10.1155/2013/956792. · DOI · Paper page
  139. Ponti, G., Maccaferri, M., Ruini, C., Tomasi, A., Ozben, T., 2020. Biomarkers associated with COVID-19 disease progression. Crit. Rev. Clin. Lab. Sci. 57, 389-399. https:// doi.org/10.1080/10408363.2020.1770685. · DOI
  140. Qiu, Z., Sweeney, D.D., Netzeband, J.G., Gruol, D.L., 1998. Chronic interleukin-6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons. J. Neurosci. 18, 10445-10456. https://doi.org/10.1523/ JNEUROSCI.18-24-10445.1998. · DOI
  141. Quaglia, L.A., Freitas, W.M., Soares, A.A., Santos, R.D., Nadruz, W., Blaha, M., Coelho, O. R., Blumenthal, R., Agatston, A., Nasir, K., Sposito, A.C., 2014. C-reactive protein is independently associated with coronary atherosclerosis burden among octogenarians. Aging Clin. Exp. Res. 26, 19-23. https://doi.org/10.1007/s40520- 013-0114-x. · DOI
  142. Quinn, L.B.S., Anderson, B.G., Strait-Bodey, L., Wolden-Hanson, T., 2010. Serum and muscle interleukin-15 levels decrease in aging mice: Correlation with declines in soluble interleukin-15 receptor alpha expression. Exp. Gerontol. 45, 106-112. https://doi.org/10.1016/J.EXGER.2009.10.012. · DOI
  143. Ranucci, M., Ballotta, A., Di Dedda, U., Baryshnikova, E., Dei Poli, M., Resta, M., Falco, M., Albano, G., Menicanti, L., 2020. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J. Thromb. Haemost. 18, 1747-1751. https://doi.org/10.1111/jth.14854. · DOI
  144. Reich, D., Patterson, N., Ramesh, V., De Jager, P.L., McDonald, G.J., Tandon, A., Choy, E., Hu, D., Tamraz, B., Pawlikowska, L., Wassel-Fyr, C., Huntsman, S., Waliszewska, A., Rossin, E., Li, R., Garcia, M., Reiner, A., Ferrell, R., Cummings, S., Kwok, P.-Y., Harris, T., Zmuda, J.M., Ziv, E., 2007. Admixture Mapping of an Allele Affecting Interleukin 6 Soluble Receptor and Interleukin 6 Levels. Am. J. Hum. Genet. 80, 716-726. https://doi.org/10.1086/513206. · DOI
  145. Reuben, D.B., Ferrucc, L., Wallace, R., Tracy, R.P., Corti, M.C., Heimovitz, H., Harris, T. B., 2000. The prognostic value of serum albumin in healthy older persons with low and high serum interleukin-6 (IL-6) levels. J. Am. Geriatr. Soc. 48, 1404-1407. https://doi.org/10.1111/j.1532-5415.2000.tb02629.x. · DOI · Paper page
  146. Ridker, P.M., Luscher, T.F., 2014. Anti-inflammatory therapies for cardiovascular disease. Eur. Heart J. 35, 1782-1791. https://doi.org/10.1093/eurheartj/ehu203. · DOI
  147. Riethmueller, S., Somasundaram, P., Ehlers, J.C., Hung, C.-W., Flynn, C.M., Lokau, J., Agthe, M., Düsterhöft, S., Zhu, Y., Grötzinger, J., Lorenzen, I., Koudelka, T., Yamamoto, K., Pickhinke, U., Wichert, R., Becker-Pauly, C., Rädisch, M., Albrecht, A., Hessefort, M., Stahnke, D., Unverzagt, C., Rose-John, S., Tholey, A., Garbers, C., 2017. Proteolytic origin of the soluble human IL-6R in vivo and a decisive role of N-glycosylation. PLOS Biol. 15, e2000080 https://doi.org/10.1371/ journal.pbio.2000080. · DOI
  148. Rodríguez-Hernández, M. Á., Carneros, D., Núñez-Núñez, M., Coca, R., Baena, R., López- Ruiz, G.M., Cano-Serrano, M.E., Martínez-Tellería, A., Fuentes-López, A., Praena- Fernandez, J.M., Garbers, C., Hernández-Quero, J., García, F., Rose-John, S., Bustos, M., 2022. Identification of IL-6 signalling components as predictors of severity and outcome in COVID-19. Front. Immunol. 13. https://doi.org/10.3389/ fimmu.2022.891456. · DOI
  149. Rong, Y.-D., Bian, A.-L., Hu, H.-Y., Ma, Y., Zhou, X.-Z., 2018. Study on relationship between elderly sarcopenia and inflammatory cytokine IL-6, anti-inflammatory cytokine IL-10. BMC Geriatr. 18, 308. https://doi.org/10.1186/s12877-018-1007-9. · DOI
  150. Roodman, G.D., Kurihara, N., Ohsaki, Y., Kukita, A., Hosking, D., Demulder, A., Smith, J. F., Singer, F.R., 1992. Interleukin 6. A potential autocrine/paracrine factor in Paget's disease of bone. J. Clin. Invest 89, 46-52. https://doi.org/10.1172/JCI115584. · DOI
  151. Rosas, I.O., Bräu, N., Waters, M., Go, R., Hunter, B.D., Bhagani, S., Skiest, D., Aziz, M.S., Cooper, N., Douglas, I.S., Savic, S., Youngstein, T., Del Sorbo, L., Cubillo Gracian, A., De La Zerda, D.J., Ustianowski, A., Bao, M., Dimonaco, S., Graham, E., Matharu, B., Spotswood, H., Tsai, L., Malhotra, A., Peters, J.J., 2020. Tocilizumab in hospitalized patients With COVID-19 pneumonia. medRxiv. https://doi.org/10.1101/ 2020.08.27.20183442. · DOI
  152. Rose-John, S., 2018. Interleukin-6 family cytokines. Cold Spring Harb. Perspect. Biol. 10, a028415 https://doi.org/10.1101/CSHPERSPECT.A028415. · DOI
  153. Rupert, J.E., Narasimhan, A., Jengelley, D.H.A., Jiang, Y., Liu, J., Au, E., Silverman, L.M., Sandusky, G., Bonetto, A., Cao, S., Lu, X., O'Connell, T.M., Liu, Y., Koniaris, L.G., Zimmers, T.A., 2021. Tumor-derived IL-6 and trans-signaling among tumor, fat, and muscle mediate pancreatic cancer cachexia. J. Exp. Med. 218 https://doi.org/ 10.1084/jem.20190450. · DOI
  154. Sabaka, P., Koščálová, A., Straka, I., Hodosy, J., Lipták, R., Kmotorková, B., Kachlíková, M., Kušnírová, A., 2021. Role of interleukin 6 as a predictive factor for a severe course of Covid-19: retrospective data analysis of patients from a long-term care facility during Covid-19 outbreak. BMC Infect. Dis. 21, 308. https://doi.org/ 10.1186/s12879-021-05945-8. · DOI · Paper page
  155. Sacks, D., Baxter, B., Campbell, B.C.V., Carpenter, J.S., Cognard, C., Dippel, D., Eesa, M., Fischer, U., Hausegger, K., Hirsch, J.A., Shazam Hussain, M., Jansen, O., Jayaraman, M.V., Khalessi, A.A., Kluck, B.W., Lavine, S., Meyers, P.M., Ramee, S., Rüfenacht, D.A., Schirmer, C.M., Vorwerk, D., 2018. Multisociety consensus quality improvement revised consensus statement for endovascular therapy of acute ischemic stroke. Int. J. Stroke 13, 612-632. https://doi.org/10.1177/ 1747493018778713. · DOI
  156. Salvarani, C., Dolci, G., Massari, M., Merlo, D.F., Cavuto, S., Savoldi, L., Bruzzi, P., Boni, F., Braglia, L., Turrà, C., Ballerini, P.F., Sciascia, R., Zammarchi, L., Para, O., Scotton, P.G., Inojosa, W.O., Ravagnani, V., Salerno, N.D., Sainaghi, P.P., Brignone, A., Codeluppi, M., Teopompi, E., Milesi, M., Bertomoro, P., Claudio, N., Salio, M., Falcone, M., Cenderello, G., Donghi, L., Del Bono, V., Colombelli, P.L., Angheben, A., Passaro, A., Secondo, G., Pascale, R., Piazza, I., Facciolongo, N., Costantini, M., 2021. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia. JAMA Intern. Med. 181, 24. https://doi.org/10.1001/jamainternmed.2020.6615. · DOI
  157. Sang, E.R., Tian, Y., Miller, L.C., Sang, Y., 2021. Epigenetic evolution of ACE2 and IL-6 genes: non-canonical interferon-stimulated genes correlate to COVID-19 susceptibility in vertebrates. Genes 12. https://doi.org/10.3390/genes12020154. · DOI
  158. Saver, J.L., Goyal, M., Bonafe, A., Diener, H.-C., Levy, E.I., Pereira, V.M., Albers, G.W., Cognard, C., Cohen, D.J., Hacke, W., Jansen, O., Jovin, T.G., Mattle, H.P., Nogueira, R.G., Siddiqui, A.H., Yavagal, D.R., Baxter, B.W., Devlin, T.G., Lopes, D.K., Reddy, V.K., du Mesnil de Rochemont, R., Singer, O.C., Jahan, R., 2015. Stent- retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N. Engl. J. Med 372, 2285-2295. https://doi.org/10.1056/NEJMoa1415061. · DOI
  159. Scambia, G., Testa, U., Panici, P.B., Martucci, R., Foti, E., Petrini, M., Amoroso, M., Masciullo, V., Peschle, C., Mancuso, S., 1994. Interleukin-6 serum levels in patients with gynecological tumors. Int. J. Cancer 57, 318-323. https://doi.org/10.1002/ IJC.2910570305. · DOI
  160. Schaap, L.A., Pluijm, S.M.F., Deeg, D.J.H., Visser, M., 2006. Inflammatory markers and loss of muscle mass (Sarcopenia) and strength. Am. J. Med. 119, 526.e9-526.e17. https://doi.org/10.1016/J.AMJMED.2005.10.049. · DOI · Paper page
  161. Schaper, F., Rose-John, S., 2015. Interleukin-6: biology, signaling and strategies of blockade. Cytokine Growth Factor Rev. 26, 475-487. https://doi.org/10.1016/J. CYTOGFR.2015.07.004. · DOI
  162. Scheller, J., Chalaris, A., Schmidt-Arras, D., Rose-John, S., 2011. The pro-and anti- inflammatory properties of the cytokine interleukin-6. Biochim. Biophys. Acta Mol. Cell Res. https://doi.org/10.1016/j.bbamcr.2011.01.034. · DOI · Paper page
  163. Schumacher, N., Meyer, D., Mauermann, A., Von Der Heyde, J., Wolf, J., Schwarz, J., Knittler, K., Murphy, G., Michalek, M., Garbers, C., Bartsch, J.W., Guo, S., Schacher, B., Eickholz, P., Chalaris, A., Rose-John, S., Rabe, B., 2015. Shedding of endogenous interleukin-6 receptor (IL-6R) is governed by a disintegrin and metalloproteinase (ADAM) proteases while a full-length IL-6R isoform localizes to circulating microvesicles. J. Biol. Chem. 290, 26059-26071. https://doi.org/ 10.1074/JBC.M115.649509. · DOI
  164. Schumacher, N., Schmidt, S., Schwarz, J., Dohr, D., Lokau, J., Scheller, J., Garbers, C., Chalaris, A., Rose-John, S., Rabe, B., 2016. Circulating soluble IL-6R but Not ADAM17 activation drives mononuclear cell migration in tissue inflammation. J. Immunol. 197, 3705-3715. https://doi.org/10.4049/jimmunol.1600909. · DOI
  165. Senchenkova, E.Y., Komoto, S., Russell, J., Almeida-Paula, L.D., Yan, L.-S., Zhang, S., Granger, D.N., 2013. Interleukin-6 mediates the platelet abnormalities and thrombogenesis associated with experimental colitis. Am. J. Pathol. 183, 173-181. https://doi.org/10.1016/j.ajpath.2013.03.014. · DOI
  166. Skiniotis, G., Boulanger, M.J., Garcia, K.C., Walz, T., 2005. Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor. Nat. Struct. Mol. Biol. 12, 545-551. https://doi.org/10.1038/NSMB941. · DOI
  167. Smits, S.L., de Lang, A., van den Brand, J.M.A., Leijten, L.M., van IJcken, W.F., Eijkemans, M.J.C., van Amerongen, G., Kuiken, T., Andeweg, A.C., Osterhaus, A.D. M.E., Haagmans, B.L., 2010. Exacerbated innate host response to SARS-CoV in aged non-human primates. PLoS Pathog. 6, e1000756 https://doi.org/10.1371/journal. ppat.1000756. · DOI
  168. Sommer, J., Garbers, C., Wolf, J., Trad, A., Moll, J.M., Sack, M., Fischer, R., Grötzinger, J., Waetzig, G.H., Floss, D.M., Scheller, J., 2014. Alternative intronic polyadenylation generates the interleukin-6 trans-signaling inhibitor sgp130-E10. J. Biol. Chem. 289, 22140-22150. https://doi.org/10.1074/jbc.M114.560938. · DOI
  169. Storci, G., De Carolis, S., Papi, A., Bacalini, M.G., Gensous, N., Marasco, E., Tesei, A., Fabbri, F., Arienti, C., Zanoni, M., Sarnelli, A., Santi, S., Olivieri, F., Mensà, E., Latini, S., Ferracin, M., Salvioli, S., Garagnani, P., Franceschi, C., Bonafè, M., 2019. Genomic stability, anti-inflammatory phenotype, and up-regulation of the RNAseH2 in cells from centenarians. Cell Death Differ. 269 (26), 1845-1858. https://doi.org/ 10.1038/s41418-018-0255-8. · DOI
  170. Strohbehn, G.W., Heiss, B.L., Rouhani, S.J., Trujillo, J.A., Yu, J., Kacew, A.J., Higgs, E.F., Bloodworth, J.C., Cabanov, A., Wright, R.C., Koziol, A.K., Weiss, A., Danahey, K., Karrison, T.G., Edens, C.C., Bauer Ventura, I., Pettit, N.N., Patel, B.K., Pisano, J., Strek, M.E., Gajewski, T.F., Ratain, M.J., Reid, P.D., 2021. COVIDOSE: a phase II clinical trial of low-dose tocilizumab in the treatment of noncritical COVID-19 pneumonia. Clin. Pharmacol. Ther. 109, 688-696. https://doi.org/10.1002/ cpt.2117. · DOI
  171. Tanaka, T., Narazaki, M., Kishimoto, T., 2014. IL-6 in inflammation, immunity, and disease. Cold Spring Harb. Perspect. Biol. 6, a016295 https://doi.org/10.1101/ cshperspect.a016295. · DOI · Paper page
  172. Terry, C.F., Loukaci, V., Green, F.R., 2000. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. J. Biol. Chem. 275, 18138-18144. https://doi.org/10.1074/JBC.M000379200. · DOI
  173. Toulmond, S., Vige, X., Fage, D., Benavides, J., 1992. Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons. Neurosci. Lett. 144, 49-52. https://doi.org/10.1016/0304-3940(92)90713-h. · DOI
  174. Trichopoulos, D., Psaltopoulou, T., Orfanos, P., Trichopoulou, A., Boffetta, P., 2006. Plasma C-reactive protein and risk of cancer: a prospective study from Greece. Cancer Epidemiol. Biomark. Prev. 15, 381-384. https://doi.org/10.1158/1055- 9965.EPI-05-0626. · DOI
  175. Tu, Y.-F., Chien, C.-S., Yarmishyn, A.A., Lin, Y.-Y., Luo, Y.-H., Lin, Y.-T., Lai, W.-Y., Yang, D.-M., Chou, S.-J., Yang, Y.-P., Wang, M.-L., Chiou, S.-H., 2020. A review of SARS-CoV-2 and the ongoing clinical trials. Int. J. Mol. Sci. 21, 2657. https://doi. org/10.3390/ijms21072657. · DOI
  176. Tumu, V.R., Govatati, S., Guruvaiah, P., Deenadayal, M., Shivaji, S., Bhanoori, M., 2013. An interleukin-6 gene promoter polymorphism is associated with polycystic ovary syndrome in South Indian women. J. Assist. Reprod. Genet. 30, 1541-1546. https:// doi.org/10.1007/S10815-013-0111-1. · DOI
  177. Ulhaq, Z.S., Soraya, G.V., 2020. Interleukin-6 as a potential biomarker of COVID-19 progression. Médecine Mal. Infect. 50, 382-383. https://doi.org/10.1016/j. medmal.2020.04.002. · DOI
  178. Vanden Berghe, W., Vermeulen, L., De Wilde, G., De Bosscher, K., Boone, E., Haegeman, G., 2000. Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6. Biochem. Pharmacol. 60, 1185-1195. https://doi.org/10.1016/S0006-2952(00)00412-3. · DOI
  179. Vasan, R.S., Sullivan, L.M., Roubenoff, R., Dinarello, C.A., Harris, T., Benjamin, E.J., Sawyer, D.B., Levy, D., Wilson, P.W.F., D'Agostino, R.B., 2003. Inflammatory markers and risk of heart failure in elderly subjects without prior myocardial infarction: the Framingham Heart Study. Circulation 107, 1486-1491. https://doi. org/10.1161/01.CIR.0000057810.48709.F6. · DOI
  180. Velavan, T.P., Meyer, C.G., 2020. Mild versus severe COVID-19: laboratory markers. Int. J. Infect. Dis. 95, 304-307. https://doi.org/10.1016/j.ijid.2020.04.061. · DOI
  181. Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M., Stockinger, B., 2006. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179-189. https://doi.org/10.1016/j. immuni.2006.01.001. · DOI · Paper page
  182. Veverka, V., Baker, T., Redpath, N.T., Carrington, B., Muskett, F.W., Taylor, R.J., Lawson, A.D.G., Henry, A.J., Carr, M.D., 2012. Conservation of functional sites on interleukin-6 and implications for evolution of signaling complex assembly and therapeutic intervention. J. Biol. Chem. 287, 40043-40050. https://doi.org/ 10.1074/JBC.M112.405597. · DOI
  183. Von Linsingen, R., Bompeixe, E.P., Da Graca Bicalho, M., 2005. A case-control study in IL6 and TGFB1 gene polymorphisms and recurrent spontaneous abortion in southern brazilian patients. Am. J. Reprod. Immunol. 53, 94-99. https://doi.org/10.1111/ j.1600-0897.2005.00250.x. · DOI
  184. Wang, Y., Fuller, G.M., 2017. Phosphorylation and internalization of gp130 occur after IL-6 activation of Jak2 kinase in hepatocytes. https://doi.org/10.1091/mbc.5.7.819 5, 819-828. 〈https://doi.org/10.1091/MBC.5.7.819〉. · DOI
  185. Warren, K.N., Beason-Held, L.L., Carlson, O., Egan, J.M., An, Y., Doshi, J., Davatzikos, C., Ferrucci, L., Resnick, S.M., 2018. Elevated markers of inflammation are associated with longitudinal changes in brain function in older adults. J. Gerontol. Ser. A 73, 770-778. https://doi.org/10.1093/gerona/glx199. · DOI
  186. Wassel, C.L., Barrett-Connor, E., Laughlin, G.A., 2010. Association of circulating C- reactive protein and interleukin-6 with longevity into the 80s and 90s: the rancho bernardo study. J. Clin. Endocrinol. Metab. 95, 4748. https://doi.org/10.1210/ JC.2010-0473. · DOI
  187. Weinstein, D.A., Roy, C.N., Fleming, M.D., Loda, M.F., Wolfsdorf, J.I., Andrews, N.C., 2002. Inappropriate expression of hepcidin is associated with iron refractory anemia: implications for the anemia of chronic disease. Blood 100, 3776-3781. https://doi. org/10.1182/BLOOD-2002-04-1260. · DOI · Paper page
  188. Weisel, J.W., Litvinov, R.I., 2013. Mechanisms of fibrin polymerization and clinical implications. Blood 121, 1712-1719. https://doi.org/10.1182/BLOOD-2012-09- 306639. · DOI
  189. Wells, J.C.K., 2011. The thrifty phenotype: an adaptation in growth or metabolism? Am. J. Hum. Biol. 23, 65-75. https://doi.org/10.1002/ajhb.21100. · DOI
  190. Weng, N., 2006. Aging of the immune system: how much can the adaptive immune system adapt? Immunity 24, 495-499. https://doi.org/10.1016/j. immuni.2006.05.001. · DOI
  191. Wilkinson, A.N., Gartlan, K.H., Kelly, G., Samson, L.D., Olver, S.D., Avery, J., Zomerdijk, N., Tey, S.-K., Lee, J.S., Vuckovic, S., Hill, G.R., 2018. Granulocytes are unresponsive to IL-6 due to an absence of gp130. J. Immunol. 200, 3547-3555. https://doi.org/10.4049/jimmunol.1701191. · DOI
  192. Wolf, J., Waetzig, G.H., Chalaris, A., Reinheimer, T.M., Wege, H., Rose-John, S., Garbers, C., 2016a. Different soluble forms of the interleukin-6 family signal transducer gp130 fine-tune the blockade of interleukin-6 trans-signaling. J. Biol. Chem. 291, 16186-16196. https://doi.org/10.1074/jbc.M116.718551. · DOI
  193. Wolf, J., Waetzig, G.H., Reinheimer, T.M., Scheller, J., Rose-John, S., Garbers, C., 2016b. A soluble form of the interleukin-6 family signal transducer gp130 is dimerized via a C-terminal disulfide bridge resulting from alternative mRNA splicing. Biochem. Biophys. Res. Commun. 470, 870-876. https://doi.org/10.1016/j.bbrc.2016.01.127. · DOI
  194. Wu, X., Zheng, W., Jin, P., Hu, J., Zhou, Q., 2019. Role of IGFBP1 in the senescence of vascular endothelial cells and severity of aging-related coronary atherosclerosis. Int. J. Mol. Med. https://doi.org/10.3892/ijmm.2019.4338. · DOI
  195. Wyczalkowska-Tomasik, A., Czarkowska-Paczek, B., Zielenkiewicz, M., Paczek, L., 2016. Inflammatory markers change with age, but do not fall beyond reported normal ranges. Arch. Immunol. Ther. Exp. (Warsz. ). 64, 249-254. https://doi.org/10.1007/ s00005-015-0357-7. · DOI
  196. Yang, M.-L., Wang, C.-T., Yang, S.-J., Leu, C.-H., Chen, S.-H., Wu, C.-L., Shiau, A.-L., 2017. IL-6 ameliorates acute lung injury in influenza virus infection. Sci. Rep. 7, 43829. https://doi.org/10.1038/srep43829. · DOI
  197. Ye, S.M., Johnson, R.W., 1999. Increased interleukin-6 expression by microglia from brain of aged mice. J. Neuroimmunol. 93, 139-148. https://doi.org/10.1016/ S0165-5728(98)00217-3. · DOI
  198. Zhai, P., Ding, Y., Wu, X., Long, J., Zhong, Y., Li, Y., 2020. The epidemiology, diagnosis and treatment of COVID-19. Int. J. Antimicrob. Agents 55, 105955. https://doi.org/ 10.1016/j.ijantimicag.2020.105955. · DOI
  199. Zhang, C., Wu, Z., Li, J.-W., Zhao, H., Wang, G.-Q., 2020. Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int. J. Antimicrob. Agents 55, 105954. https://doi.org/10.1016/j. ijantimicag.2020.105954. · DOI
  200. Zhang, J.G., Zhang, Y., Owczarek, C.M., Ward, L.D., Moritz, R.L., Simpson, R.J., Yasukawa, K., Nicola, N.A., 1998. Identification and characterization of two distinct truncated forms of gp130 and a soluble form of leukemia inhibitory factor receptor α-chain in normal human urine and plasma *. J. Biol. Chem. 273, 10798-10805. https://doi.org/10.1074/JBC.273.17.10798. · DOI

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Cited by

Sorted by citations

Authors
Forcina, L., Franceschi, C., & Musarò, A.
Affiliations
  • Sapienza University of Rome (IT)
  • University of Bologna (IT)
  • Istituto Pasteur (IT)
Corresponding author
Musarò, Antonio
ORCID
Venue
Ageing Research Reviews
Publisher
Elsevier BV
Published
2022-09
Volume
80
Pages
101697
ISSN
1568-1637 (ISSN-L)
DOI
10.1016/j.arr.2022.101697
OpenAlex
W4285604466
Cited by
85
References
28
Citations by year
2026: 14 · 2025: 25 · 2024: 25 · 2023: 20 · 2022: 1
FWCI
2.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Ageing Research Reviews (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nc-nd)
Funders
  • Fondazione Roma
  • Agenzia Spaziale Italiana (MARS-PRE 2019-11-U.0, RF-2016-02364503)
  • AFM-Téléthon (23608)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
interleukin-6, hormesis, aging, age-related diseases, chronic inflammation, oxidative stress, skeletal muscle, myogenesis, fibrosis, cytokine signaling
MeSH terms
Aging, Dose-Response Relationship, Immunologic, Gene Expression Regulation, Humans, Inflammation, Signal Transduction, Interleukin-6, Oxidative Stress

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