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Interleukin-6
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Interleukin-6 (IL-6) is a cytokine of a pro-inflammatory nature, and it can be produced by various cell types of the immune system as well as by some nonimmune cells, including fibroblasts. IL-6 is cytokine important for the initial phase of immune response that is recognized by 2 types of receptor. Overproduction of IL-6 is associated with aging, chronic inflammation, cancer and severe viral infections such is COVID-19.  This molecule is not produced by immune cells but also by cancer-associated fibroblasts and cancer cells. Control of its production or inhibition of IL-6 receptors could have the therapeutic consequences. 

IL-6 IL-6 receptor Cancer Aging COVID-19 Cancer-associated fibroblast
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1. Introduction

Interleukin-6 (IL-6) is a bioactive protein known under numerous synonyms (Table 1). Regarding the anatomical distribution of Il-6, it was identified in the lungs, urinary bladder, adipose tissue, muscles, vermiform appendix, etc. (The Human Protein Atlas, [1]​).

Table 1. Synonyms for interleukin-6 (IL-6).

Name

Author

Interferon β-2

Zilberstein et al., 1986[2]

26K factor

Haegeman et al., 1986[3]

B-cell stimulatory factor

Hirano et al., 1985[4]

Hybridoma growth factor

Brakenhoff et al., 1987[5]

Plasmacytoma growth factor

Nordan et al., 1987[6]

Hepatocyte stimulatory factor

Gauldie et al., 1987[7]

Haematopoietic factor

Ikebuchi et al., 1987[8]

Cytotoxic T-cell differentiation factor

Takai et al., 1988[9]

The main cell types acting as producers of IL-6 are shortlisted in Table 2.

Table 2. Examples of cells producing IL-6.

Type of cell

Author

Keratinocyte

Groeger and Meyle, 2019[10]

Enterocyte

Pritts et al., 2002[11]

Urothelium

Uehling et al., 1999[12]

Hepatocyte

Schmidt-Arras and Rose-John, 2016[13]

Pneumocyte and bronchial epithelial cell

Cheung, 2005[14]

Smooth muscle

Kyotani et al., 2019[15]

Skeletal muscle

Barbalho et al., 2020[16]

Osteoblast

Kovács et al., 2019[17]

Adipocyte

Xie et al., 2019[18]

Macrophage

Shapouri-Moghaddam et al., 2018[19]

Neuron

Shapouri-Moghaddam et al., 2018[19]

IL-6 is recognised by its transmembrane receptor (IL-6R), which forms a complex with glycoprotein 130 (gp130). This receptor has tyrosine kinase activity and activates signal transducer and activator of transcription 3 (STAT3) via phosphorylation. On the other hand, the extracellular portion of IL-6R can be cleaved from the intramembranous domain of the receptor by membrane protease ADAM-17. Soluble IL-6R without tyrosine kinase activity interacts with gp130 outside the cell and forms a complex of IL-6, soluble IL-6R and gp130, which is docked back to the cell membrane[20]. This arrangement of the IL-6–IL-6R axis can be functionally variable when the actual function of IL-6 signalling is dependent on the type of cell and the type of interacting receptor. While the interaction of IL-6 with transmembrane IL-6R and gp130 participates in anti-inflammatory pro-cancerogenic signalling, the interaction of IL-6 with soluble IL-6R and gp130 stimulates inflammation[20].

2. Physiological Functions of IL-6

The family of IL-6-related proteins consists of members with remarkable and distinct biological activities that are structurally similar to IL-6, such as IL-11, IL-31, cardiotrophin-1, ciliary neurotrophic factor (CNTF), cardiotrophin-like cytokine (CLC), granulocyte colony-stimulating factor (G-CSF), leptin, leukaemia inhibitory factor (LIF), neuropoietin, and oncostatin[21]. This cytokine family is defined by sharing common IL-6 family signalling receptor gp130 more than by any structural homology of its members. It is therefore not surprising that the IL-6 family cytokines not only display partially overlapping, but also, more significantly, very different biological activities[22].

IL-6 knockout mice are available for research purposes[23]. Interestingly, their embryonic and foetal development is not hampered, and knockout animals do not have any apparent developmental abnormalities. On the other hand, these mouse strains were highly susceptible to several pathogens, and they failed to generate acute-phase responses[24].

IL-6 contributes to the host defence by stimulation of the acute phase immune response, including elevation of body temperature[25]. In this context, IL-6 positively influences the maturation of B lymphocytes and cytotoxic T lymphocytes[26][27]. In the same motion, IL-6 deficiency in an experimental model leads to protection against triggering autoimmune encephalomyelitis[28].

IL-6 also belongs to the family of myokines such as IL-8, IL-15, irisin, myostatin, fibroblast growth factor (FGF)21, leukemia inhibitory factor (LIF), brain-derived neurotrophic factor (BDNF), and insulin like growth factor-1 (IGF-1) that influence the function of skeletal muscle with metabolic impacts on the whole organism[16], namely by interaction with adipocytes and factors produced by these cells[29]. In knockout mice, surviving animals had reduced age-related obesity development[30].

The role of IL-6 in the bone metabolism was also confirmed by the stimulation of osteoclast activity[31]. This is in good agreement with the observed protection against the bone loss after ovariectomy in a mouse knockout model[32].

The function of IL-6 in the aging, cancer and viral infection is discussed.

These few examples demonstrate the complex and multifaceted role of IL-6 both in physiological and pathological conditions in the human body.

References

  1. Tissue Expression of IL6—Summary—The Human Protein Atlas. Available online: https://www.proteinatlas.org/ENSG00000136244-IL6/tissue
  2. A. Zilberstein; R. Ruggieri; J.H. Korn; M. Revel; Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines.. The EMBO Journal 1986, 5, 2529-2537, 10.1002/j.1460-2075.1986.tb04531.x.
  3. Guy Haegeman; Jean Content; Guido Volckaert; Rik Derynck; Jan Tavernier; Walter Fiers; Structural analysis of the sequence coding for an inducible 26-kDa protein in human fibroblasts. JBIC Journal of Biological Inorganic Chemistry 1986, 159, 625-632, 10.1111/j.1432-1033.1986.tb09931.x.
  4. T. Hirano; T. Taga; N. Nakano; K. Yasukawa; S. Kashiwamura; K. Shimizu; K. Nakajima; K. H. Pyun; T. Kishimoto; Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2).. Proceedings of the National Academy of Sciences 1985, 82, 5490-5494, 10.1073/pnas.82.16.5490.
  5. J P Brakenhoff; E R De Groot; R F Evers; H Pannekoek; L A Aarden; Molecular cloning and expression of hybridoma growth factor in Escherichia coli.. The Journal of Immunology 1987, 139, 4116-4121, .
  6. R P Nordan; J G Pumphrey; S Rudikoff; Purification and NH2-terminal sequence of a plasmacytoma growth factor derived from the murine macrophage cell line P388D1.. The Journal of Immunology 1987, 139, 813-817, .
  7. J. Gauldie; C. Richards; D. Harnish; P. Lansdorp; H. Baumann; Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells.. Proceedings of the National Academy of Sciences 1987, 84, 7251-7255, 10.1073/pnas.84.20.7251.
  8. K. Ikebuchi; G. G. Wong; S. C. Clark; J. N. Ihle; Y. Hirai; M. Ogawa; Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hemopoietic progenitors.. Proceedings of the National Academy of Sciences 1987, 84, 9035-9039, 10.1073/pnas.84.24.9035.
  9. Y Takai; G G Wong; S C Clark; S J Burakoff; S H Herrmann; B cell stimulatory factor-2 is involved in the differentiation of cytotoxic T lymphocytes.. The Journal of Immunology 1988, 140, 140, .
  10. Sabine Groeger; Joerg Meyle; Oral Mucosal Epithelial Cells. Frontiers in Immunology 2019, 10, 208, 10.3389/fimmu.2019.00208.
  11. Timothy Pritts; Eric Hungness; Quan Wang; Bruce Robb; Dan Hershko; Per-Olof Hasselgren; Mucosal and enterocyte IL-6 production during sepsis and endotoxemia--role of transcription factors and regulation by the stress response.. The American Journal of Surgery 2002, 183, 372-383, 10.1016/s0002-9610(02)00812-7.
  12. David T. Uehling; D. Brooke Johnson; Walter J. Hopkins; The urinary tract response to entry of pathogens. World Journal of Urology 1999, 17, 351-358, 10.1007/s003450050160.
  13. Dirk Schmidt-Arras; Stefan Rose-John; IL-6 pathway in the liver: From physiopathology to therapy. Journal of Hepatology 2016, 64, 1403-1415, 10.1016/j.jhep.2016.02.004.
  14. Chung Y. Cheung; Leo L. M. Poon; Iris H. Y. Ng; Winsie Luk; Sin-Fun Sia; Mavis H. S. Wu; Kwok-Hung Chan; Kwok-Yung Yuen; Siamon Gordon; Yi Guan; et al. Cytokine Responses in Severe Acute Respiratory Syndrome Coronavirus-Infected Macrophages In Vitro: Possible Relevance to Pathogenesis. Journal of Virology 2005, 79, 7819-7826, 10.1128/jvi.79.12.7819-7826.2005.
  15. Yoji Kyotani; Shin Takasawa; Masanori Yoshizumi; Proliferative Pathways of Vascular Smooth Muscle Cells in Response to Intermittent Hypoxia.. International Journal of Molecular Sciences 2019, 20, 2706, 10.3390/ijms20112706.
  16. Sandra M. Barbalho; Edmundo V. Prado Neto; Ricardo De Alvares Goulart; Marcelo D. Bechara; Eduardo F. Baisi Chagas; Mauro Audi; Leila M. Guissoni Campos; Elen Landgraf Guiger; Rogério L. Buchaim; Daniela V. Buchaim; et al. Myokines: a descriptive review. The Journal of Sports Medicine and Physical Fitness 2020, 60, null, 10.23736/s0022-4707.20.10884-3.
  17. Béla Kovács; Enikő Vajda; Előd Ernő Nagy; Regulatory Effects and Interactions of the Wnt and OPG-RANKL-RANK Signaling at the Bone-Cartilage Interface in Osteoarthritis.. International Journal of Molecular Sciences 2019, 20, 4653, 10.3390/ijms20184653.
  18. Chenxi Xie; Qian Chen; Adipokines: New Therapeutic Target for Osteoarthritis?. Current Rheumatology Reports 2019, 21, 71, 10.1007/s11926-019-0868-z.
  19. Abbas Shapouri Moghadam; Saeed Mohammadian; Hossein Vazini; Mahdi Taghadosi; Seyed-Alireza Esmaeili; Fatemeh Mardani; Bita Seifi; Asadollah Mohammadi; Jalil Tavakol Afshari; Amirhossein Sahebkar; et al. Macrophage plasticity, polarization, and function in health and disease. Journal of Cellular Physiology 2018, 233, 6425-6440, 10.1002/jcp.26429.
  20. Lukáš Lacina; Jan Brábek; Vladimír Král; Ondřej Kodet; Karel Smetana; Interleukin-6: a molecule with complex biological impact in cancer.. Histol. Histopathol. 2018, 34, 125-136, .
  21. Nese Unver; Florencia McAllister; IL-6 family cytokines: Key inflammatory mediators as biomarkers and potential therapeutic targets. Cytokine & Growth Factor Reviews 2018, 41, 10-17, 10.1016/j.cytogfr.2018.04.004.
  22. Stefan Rose-John; Interleukin-6 Family Cytokines. Cold Spring Harbor Perspectives in Biology 2017, 10, a028415, 10.1101/cshperspect.a028415.
  23. Manfred Kopf; Heinz Baumann; Giulia Freer; Marina A Freudenberg; Marinus C Lamers; Tadamitsu Kishimoto; Rolf M Zinkernagel; Horst Bluethmann; Georges Köhler; Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 1994, 368, 339-342, 10.1038/368339a0.
  24. Ramsay, A.J.; Kopf, M. IL-6 Gene Knockout Mice. In Cytokine Knockouts. Contemporary Immunology; Durum, S.K., Muegge, K., Eds.; Humana Press: Totowa, NJ, USA, 1998; pp. 227–236.
  25. Toshio Tanaka; Masashi Narazaki; Tadamitsu Kishimoto; IL-6 in Inflammation, Immunity, and Disease. Cold Spring Harbor Perspectives in Biology 2014, 6, a016295-a016295, 10.1101/cshperspect.a016295.
  26. Takatsuki, F.; Okano, A.; Suzuki, C.; Chieda, R.; Takahara, Y.; Hirano, T.; Kishimoto, T.; Hamuro, J.; Akiyama, Y. Human recombinant IL-6/B cell stimulatory factor 2 augments murine antigen-specific antibody responses in vitro and in vivo. J. Immunol. 1988, 141, 3072–3077.
  27. Luger, T.A.; Krutmann, J.; Kirnbauer, R.; Urbanski, A.; Schwarz, T.; Klappacher, G.; Köck, A.; Micksche, M.; Malejczyk, J.; Schauer, E. IFN-beta 2/IL-6 augments the activity of human natural killer cells. J. Immunol. 1989, 143, 1206–1209.
  28. Itzhack Mendel; Anne Katz; Natacha Kozak; Avraham Ben-Nun; Michel Revel; Interleukin-6 functions in autoimmune encephalomyelitis: a study in gene-targeted mice. European Journal of Immunology 1998, 28, 1727-1737, 10.1002/(sici)1521-4141(199805)28:05<1727::aid-immu1727>3.0.co;2-#.
  29. Amaia Rodríguez; Sara Becerril; Silvia Ezquerro; Leire Méndez-Giménez; Gema Frühbeck; Crosstalk between adipokines and myokines in fat browning. Acta Physiologica 2016, 219, 362-381, 10.1111/apha.12686.
  30. Ville Wallenius; Kristina Wallenius; Bo Ahrén; Mats Rudling; Hans Carlsten; Suzanne L. Dickson; Claes Ohlsson; John-Olov Jansson; Interleukin-6-deficient mice develop mature-onset obesity. Nature Medicine 2002, 8, 75-79, 10.1038/nm0102-75.
  31. T. Tamura; N. Udagawa; N. Takahashi; C. Miyaura; S. Tanaka; Y. Yamada; Y. Koishihara; Y. Ohsugi; K. Kumaki; T. Taga; et al. Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6.. Proceedings of the National Academy of Sciences 1993, 90, 11924-11928, 10.1073/pnas.90.24.11924.
  32. V Poli; R Balena; E Fattori; A Markatos; M Yamamoto; H Tanaka; G Ciliberto; G A Rodan; F Costantini; Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion.. The EMBO Journal 1994, 13, 1189-1196, .
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View Times: 183
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Update Time: 26 Nov 2020
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    Smetana K. Interleukin-6. Encyclopedia. Available at: https://encyclopedia.pub/entry/3239. Accessed October 03, 2022.
    Smetana, Karel. "Interleukin-6," Encyclopedia, https://encyclopedia.pub/entry/3239 (accessed October 03, 2022).
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