Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

IL6RA, Interleukin-6 Receptor Subunit Alpha

  • Christoph GarbersEmail author
  • Stefan Rose-John
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101661


Historical Background

The interleukin-6 receptor (IL-6R) is a type I transmembrane protein that was cloned and described in 1988 (Yamasaki et al. 1988). It serves as the non-signaling alpha-receptor of the multifunctional cytokine IL-6 and is expressed in a cell-type-specific manner. The IL-6R shares many features with other receptors of the IL-6 family of cytokines, notably the interleukin-11 receptor (IL-11R) and the ciliary neurotrophic factor receptor (CNTFR) (Garbers et al. 2012). All these cytokines signal through the common β-receptor glycoprotein 130 (gp130).

Domain Organization and Cellular Expression of the IL-6R

The IL-6R is a prototypical type I transmembrane protein that consists of three extracellular domains. The Ig-like domain (often referred to as “D1” domain) is followed by two fibronectin type III-like domains (“D2” and “D3”), which form the so-called cytokine-binding...
This is a preview of subscription content, log in to check access.


  1. Baran P, Nitz R, Grötzinger J, Scheller J, Garbers C. Minimal interleukin (IL-)6 receptor stalk composition for IL-6R shedding and IL-6 classic signaling. J Biol Chem. 2013;288:14756–68.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Chalaris A, Garbers C, Rabe B, Rose-John S, Scheller J. The soluble interleukin 6 receptor: generation and role in inflammation and cancer. Eur J Cell Biol. 2011;90:484–94.CrossRefPubMedGoogle Scholar
  3. Csaszar E, Wang W, Usenko T, Qiao W, Delaney C, Bernstein ID, et al. Blood stem cell fate regulation by Delta-1-mediated rewiring of IL-6 paracrine signaling. Blood. 2014;123:650–8.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Garbers C, Jänner N, Chalaris A, Moss ML, Floss DM, Meyer D, et al. Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding. J Biol Chem. 2011;286:14804–11.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Garbers C, Hermanns H, Schaper F, Müller-Newen G, Grötzinger J, Rose-John S, et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 2012;23:85–97.CrossRefPubMedGoogle Scholar
  6. Garbers C, Kuck F, Aparicio-Siegmund S, Konzak K, Kessenbrock M, Sommerfeld A, et al. Cellular senescence or EGFR signaling induces interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR). Cell Cycle. 2013;12:3421–32.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Garbers C, Monhasery N, Aparicio-Siegmund S, Lokau J, Baran P, Nowell MA, et al. The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases. Biochim Biophys Acta. 2014;1842:1485–94.CrossRefPubMedGoogle Scholar
  8. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–57. doi:10.1038/ni.3153.CrossRefPubMedGoogle Scholar
  9. Jones SA, Scheller J, Rose-John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121:3375–83.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Lokau J, Nitz R, Agthe M, Monhasery N, Aparicio-Siegmund S, Schumacher N, et al. Proteolytic cleavage governs interleukin-11 trans-signaling. Cell Rep. 2016;14:1761–73.CrossRefPubMedGoogle Scholar
  11. Lütticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, Ziemiecki A, et al. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130. Science. 1994;263:89–92.CrossRefPubMedGoogle Scholar
  12. Müllberg J, Oberthür W, Lottspeich F, Mehl E, Dittrich E, Graeve L, et al. The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site. J Immunol. 1994;152:4958–68.PubMedGoogle Scholar
  13. Rafiq S, Frayling T, Murray A, Hurst A, Stevens K, Weedon M, et al. A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects. Genes Immun. 2007;8:552–9.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Riethmueller S, Ehlers JC, Lokau J, Düsterhöft S, Knittler K, Dombrowsky G, et al. Cleavage site localization differentially controls interleukin-6 receptor proteolysis by ADAM10 and ADAM17. Sci Rep. 2016;6:25550.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Rodig SJ, Meraz MA, White MJ, Lampe PA, Riley JK, Arthur CD, et al. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in cytokine-induced biologic responses. Cell. 1998;93:373–83. doi:10.1016/s0092-8674(00)81166-6.CrossRefPubMedGoogle Scholar
  16. Scheller J, Garbers C, Rose-John S. Interleukin-6: from basic biology to selective blockade of pro-inflammatory activities. Semin Immunol. 2014;26:2–12.CrossRefPubMedGoogle Scholar
  17. Stephens OW, Zhang Q, Qu P, Zhou Y, Chavan S, Tian E, et al. An intermediate-risk multiple myeloma subgroup is defined by sIL-6r: levels synergistically increase with incidence of SNP rs2228145 and 1q21 amplification. Blood. 2012;119:503–12.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Wolf J, Rose-John S, Garbers C. Interleukin-6 and its receptors: a highly regulated and dynamic system. Cytokine. 2014;70:11–20.CrossRefPubMedGoogle Scholar
  19. Yamasaki K, Taga T, Hirata Y, Yawata H, Kawanishi Y, Seed B, et al. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 1988;241:825–8.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of BiochemistryKiel UniversityKielGermany