Table of Contents Author Guidelines Submit a Manuscript
Mediators of Inflammation
Volume 2016, Article ID 1785021, 10 pages
http://dx.doi.org/10.1155/2016/1785021
Review Article

Generation of Soluble Interleukin-11 and Interleukin-6 Receptors: A Crucial Function for Proteases during Inflammation

Institute of Biochemistry, Kiel University, 24118 Kiel, Germany

Received 8 May 2016; Accepted 14 June 2016

Academic Editor: Elaine Hatanaka

Copyright © 2016 Juliane Lokau et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. T. Tanaka, M. Narazaki, and T. Kishimoto, “Therapeutic targeting of the interleukin-6 receptor,” Annual Review of Pharmacology and Toxicology, vol. 52, pp. 199–219, 2012. View at Publisher · View at Google Scholar · View at Scopus
  2. T. Tanaka, M. Narazaki, A. Ogata, and T. Kishimoto, “A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy,” Seminars in Immunology, vol. 26, no. 1, pp. 88–96, 2014. View at Publisher · View at Google Scholar · View at Scopus
  3. S. Rose-John, “Il-6 trans-signaling via the soluble IL-6 receptor: importance for the proinflammatory activities of IL-6,” International Journal of Biological Sciences, vol. 8, no. 9, pp. 1237–1247, 2012. View at Publisher · View at Google Scholar · View at Scopus
  4. S. Rose-John, J. Scheller, G. Elson, and S. A. Jones, “Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer,” Journal of Leukocyte Biology, vol. 80, no. 2, pp. 227–236, 2006. View at Publisher · View at Google Scholar · View at Scopus
  5. C. Garbers, S. Aparicio-Siegmund, and S. Rose-John, “The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition,” Current Opinion in Immunology, vol. 34, pp. 75–82, 2015. View at Publisher · View at Google Scholar · View at Scopus
  6. S. A. Jones, J. Scheller, and S. Rose-John, “Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling,” The Journal of Clinical Investigation, vol. 121, no. 9, pp. 3375–3383, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. C. Garbers and J. Scheller, “Interleukin-6 and interleukin-11: same same but different,” Biological Chemistry, vol. 394, no. 9, pp. 1145–1161, 2013. View at Publisher · View at Google Scholar · View at Scopus
  8. T. Putoczki, S. Thiem, A. Loving et al., “Interleukin-11 is the dominant Il-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically,” Cancer Cell, vol. 24, no. 2, pp. 257–271, 2013. View at Publisher · View at Google Scholar · View at Scopus
  9. M. Ernst, M. Najdovska, D. Grail et al., “STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice,” The Journal of Clinical Investigation, vol. 118, no. 5, pp. 1727–1738, 2008. View at Publisher · View at Google Scholar · View at Scopus
  10. M. Ernst and T. L. Putoczki, “Molecular pathways: IL11 as a tumor-promoting cytokine-translational implications for cancers,” Clinical Cancer Research, vol. 20, no. 22, pp. 5579–5588, 2014. View at Publisher · View at Google Scholar · View at Scopus
  11. T. Putoczki and M. Ernst, “More than a sidekick: the IL-6 family cytokine IL-11 links inflammation to cancer,” Journal of Leukocyte Biology, vol. 88, no. 6, pp. 1109–1117, 2010. View at Publisher · View at Google Scholar · View at Scopus
  12. T. L. Putoczki and M. Ernst, “IL-11 signaling as a therapeutic target for cancer,” Immunotherapy, vol. 7, no. 4, pp. 441–453, 2015. View at Publisher · View at Google Scholar · View at Scopus
  13. J. Lokau, R. Nitz, M. Agthe et al., “Proteolytic cleavage governs interleukin-11 trans-signaling,” Cell Reports, vol. 14, no. 7, pp. 1761–1773, 2016. View at Publisher · View at Google Scholar · View at Scopus
  14. C. Garbers, H. M. Hermanns, F. Schaper et al., “Plasticity and cross-talk of interleukin 6-type cytokines,” Cytokine and Growth Factor Reviews, vol. 23, no. 3, pp. 85–97, 2012. View at Publisher · View at Google Scholar · View at Scopus
  15. P. Baran, R. Nitz, J. Grötzinger, J. Scheller, and C. Garbers, “Minimal Interleukin 6 (IL-6) receptor stalk composition for IL-6 receptor shedding and IL-6 classic signaling,” The Journal of Biological Chemistry, vol. 288, no. 21, pp. 14756–14768, 2013. View at Publisher · View at Google Scholar · View at Scopus
  16. C. Stuhlmann-Laeisz, S. Lang, A. Chalaris et al., “Forced dimerization of gp130 leads to constitutive STAT3 activation, cytokine-independent growth, and blockade of differentiation of embryonic stem cells,” Molecular Biology of the Cell, vol. 17, no. 7, pp. 2986–2995, 2006. View at Publisher · View at Google Scholar · View at Scopus
  17. S. Pflanz, I. Tacken, J. Grötzinger et al., “A fusion protein of interleukin-11 and soluble interleukin-11 receptor acts as a superagonist on cells expressing gp130,” FEBS Letters, vol. 450, no. 1-2, pp. 117–122, 1999. View at Publisher · View at Google Scholar · View at Scopus
  18. T. Taga, M. Hibi, Y. Hirata et al., “Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130,” Cell, vol. 58, no. 3, pp. 573–581, 1989. View at Publisher · View at Google Scholar · View at Scopus
  19. B. Lebeau, F. A. Montero Julian, J. Wijdenes et al., “Reconstitution of two isoforms of the human interleukin-11 receptor and comparison of their functional properties,” FEBS Letters, vol. 407, no. 2, pp. 141–147, 1997. View at Publisher · View at Google Scholar · View at Scopus
  20. A. Chalaris, C. Garbers, B. Rabe, S. Rose-John, and J. Scheller, “The soluble Interleukin 6 receptor: generation and role in inflammation and cancer,” European Journal of Cell Biology, vol. 90, no. 6-7, pp. 484–494, 2011. View at Publisher · View at Google Scholar · View at Scopus
  21. M. Honda, S. Yamamoto, M. Cheng et al., “Human soluble IL-6 receptor: its detection and enhanced release by HIV infection,” Journal of Immunology, vol. 148, no. 7, pp. 2175–2180, 1992. View at Google Scholar · View at Scopus
  22. J.-P. Gaillard, R. Bataille, H. Brailly et al., “Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammopathy,” European Journal of Immunology, vol. 23, no. 4, pp. 820–824, 1993. View at Publisher · View at Google Scholar · View at Scopus
  23. F. A. Montero-Julian, “The soluble IL-6 receptors: serum levels and biological function,” Cellular and Molecular Biology, vol. 47, no. 4, pp. 583–597, 2001. View at Google Scholar · View at Scopus
  24. S. Rose-John and P. C. Heinrich, “Soluble receptors for cytokines and growth factors: generation and biological function,” Biochemical Journal, vol. 300, no. 2, pp. 281–290, 1994. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Peters, A. M. Müller, and S. Rose-John, “Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis,” Blood, vol. 92, no. 10, pp. 3495–3504, 1998. View at Google Scholar · View at Scopus
  26. H. Baumann, Y. Wang, K. K. Morella et al., “Complex of the soluble IL-11 receptor and IL-11 acts as IL-6-type cytokine in hepatic and nonhepatic cells,” Journal of Immunology, vol. 157, no. 1, pp. 284–290, 1996. View at Google Scholar · View at Scopus
  27. D. J. Curtis, D. J. Hilton, B. Roberts, L. Murray, N. Nicola, and C. G. Begley, “Recombinant soluble interleukin-11 (IL-11) receptor α-chain can act as an IL-11 antagonist,” Blood, vol. 90, no. 11, pp. 4403–4412, 1997. View at Google Scholar · View at Scopus
  28. J. Karow, K. R. Hudson, M. A. Hall et al., “Mediation of interleukin-11-dependent biological responses by a soluble form of the interleukin-11 receptor,” Biochemical Journal, vol. 318, part 2, pp. 489–495, 1996. View at Publisher · View at Google Scholar · View at Scopus
  29. G. Müller-Newen, C. Köhne, R. Keul et al., “Purification and characterization of the soluble interleukin-6 receptor from human plasma and identification of an isoform generated through alternative splicing,” European Journal of Biochemistry, vol. 236, no. 3, pp. 837–842, 1996. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Pflanz, I. Kurth, J. Grotzinger, P. C. Heinrich, and G. Muller-Newen, “Two different epitopes of the signal transducer gp130 sequentially cooperate on IL-6-induced receptor activation,” Journal of Immunology, vol. 165, no. 12, pp. 7042–7049, 2000. View at Publisher · View at Google Scholar · View at Scopus
  31. M. J. Boulanger, D.-C. Chow, E. E. Brevnova, and K. C. Garcia, “Hexameric structure and assembly of the interieukin-6/IL-6 α-receptor/gp130 complex,” Science, vol. 300, no. 5628, pp. 2101–2104, 2003. View at Publisher · View at Google Scholar · View at Scopus
  32. D.-C. Chow, X.-L. He, A. L. Snow, S. Rose-John, and K. Christopher Garcia, “Structure of an extracellular gp130 cytokine receptor signaling complex,” Science, vol. 291, no. 5511, pp. 2150–2155, 2001. View at Publisher · View at Google Scholar · View at Scopus
  33. J. Grötzinger, T. Kernebeck, K.-J. Kallen, and S. Rose-John, “IL-6 type cytokine receptor complexes: hexamer, tetramer or both?” Biological Chemistry, vol. 380, no. 7-8, pp. 803–813, 1999. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Lacroix, F. Rousseau, F. Guilhot et al., “Novel insights into interleukin 6 (IL-6) cis- and trans-signaling pathways by differentially manipulating the assembly of the IL-6 signaling complex,” The Journal of Biological Chemistry, vol. 290, no. 45, pp. 26943–26953, 2015. View at Google Scholar
  35. V. A. Barton, M. A. Hall, K. R. Hudson, and J. K. Heath, “Interleukin-11 signals through the formation of a hexameric receptor complex,” The Journal of Biological Chemistry, vol. 275, no. 46, pp. 36197–36203, 2000. View at Publisher · View at Google Scholar · View at Scopus
  36. J. Lokau and C. Garbers, “Signal transduction of interleukin-11 and interleukin-6 α-receptors,” Receptors & Clinical Investigation, vol. 3, Article ID e1190, 2016. View at Publisher · View at Google Scholar
  37. R. Nitz, J. Lokau, S. Aparicio-Siegmund, J. Scheller, and C. Garbers, “Modular organization of Interleukin-6 and Interleukin-11 α-receptors,” Biochimie, vol. 119, pp. 175–182, 2015. View at Publisher · View at Google Scholar · View at Scopus
  38. T. Jostock, J. Müllberg, S. Özbek et al., “Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses,” European Journal of Biochemistry, vol. 268, no. 1, pp. 160–167, 2001. View at Publisher · View at Google Scholar · View at Scopus
  39. J. Mauer, J. L. Denson, and J. C. Brüning, “Versatile functions for IL-6 in metabolism and cancer,” Trends in Immunology, vol. 36, no. 2, pp. 92–101, 2015. View at Publisher · View at Google Scholar
  40. D. E. Cressman, L. E. Greenbaum, R. A. DeAngelis et al., “Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice,” Science, vol. 274, no. 5291, pp. 1379–1383, 1996. View at Publisher · View at Google Scholar · View at Scopus
  41. R. Atreya, J. Mudter, S. Finotto et al., “Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo,” Nature Medicine, vol. 6, no. 5, pp. 583–588, 2000. View at Publisher · View at Google Scholar
  42. H. Schuett, R. Oestreich, G. H. Waetzig et al., “Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 32, no. 2, pp. 281–290, 2012. View at Publisher · View at Google Scholar · View at Scopus
  43. T. Barkhausen, T. Tschernig, P. Rosenstiel et al., “Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model,” Critical Care Medicine, vol. 39, no. 6, pp. 1407–1413, 2011. View at Publisher · View at Google Scholar · View at Scopus
  44. J. Hoge, I. Yan, N. Jänner et al., “IL-6 controls the innate immune response against Listeria monocytogenes via classical IL-6 signaling,” The Journal of Immunology, vol. 190, no. 2, pp. 703–711, 2013. View at Publisher · View at Google Scholar · View at Scopus
  45. A. Orazi, X. Du, Z. Yang, M. Kashai, and D. A. Williams, “Interleukin-11 prevents apoptosis and accelerates recovery of small intestinal mucosa in mice treated with combined chemotherapy and radiation,” Laboratory Investigation, vol. 75, no. 1, pp. 33–42, 1996. View at Google Scholar · View at Scopus
  46. N. S. Weich, A. Wang, M. Fitzgerald et al., “Recombinant human interleukin-11 directly promotes megakaryocytopoiesis in vitro,” Blood, vol. 90, no. 10, pp. 3893–3902, 1997. View at Google Scholar · View at Scopus
  47. T. Nakayama, A. Yoshizaki, S. Izumida et al., “Expression of interleukin-11 (IL-11) and IL-11 receptor α in human gastric carcinoma and IL-11 upregulates the invasive activity of human gastric carcinoma cells,” International Journal of Oncology, vol. 30, no. 4, pp. 825–833, 2007. View at Google Scholar · View at Scopus
  48. J. A. Lust, K. A. Donovan, M. P. Kline, P. R. Greipp, R. A. Kyle, and N. J. Maihle, “Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor,” Cytokine, vol. 4, no. 2, pp. 96–100, 1992. View at Publisher · View at Google Scholar · View at Scopus
  49. J. Müllberg, H. Schooltink, T. Stoyan et al., “The soluble interleukin-6 receptor is generated by shedding,” European Journal of Immunology, vol. 23, no. 2, pp. 473–480, 1993. View at Publisher · View at Google Scholar · View at Scopus
  50. J. Müllberg, H. Schooltink, T. Stoyan, P. C. Heinrich, and S. Rose-John, “Protein kinase C activity is rate limiting for shedding of the interleukin-6 receptor,” Biochemical and Biophysical Research Communications, vol. 189, no. 2, pp. 794–800, 1992. View at Publisher · View at Google Scholar · View at Scopus
  51. J. Mullberg, F. H. Durie, C. Otten-Evans et al., “A metalloprotease inhibitor blocks shedding of the IL-6 receptor and the p60 TNF receptor,” The Journal of Immunology, vol. 155, no. 11, pp. 5198–5205, 1995. View at Google Scholar · View at Scopus
  52. R. A. Black, C. T. Rauch, C. J. Kozlosky et al., “A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells,” Nature, vol. 385, no. 6618, pp. 729–733, 1997. View at Publisher · View at Google Scholar · View at Scopus
  53. M. L. Moss, S.-L. C. Jin, M. E. Milla et al., “Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-α,” Nature, vol. 385, no. 6618, pp. 733–736, 1997. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Scheller, A. Chalaris, C. Garbers, and S. Rose-John, “ADAM17: a molecular switch to control inflammation and tissue regeneration,” Trends in Immunology, vol. 32, no. 8, pp. 380–387, 2011. View at Publisher · View at Google Scholar · View at Scopus
  55. P. Saftig and K. Reiss, “The ‘a disintegrin and metalloproteases’ ADAM10 and ADAM17: novel drug targets with therapeutic potential?” European Journal of Cell Biology, vol. 90, no. 6-7, pp. 527–535, 2011. View at Publisher · View at Google Scholar · View at Scopus
  56. R. Khokha, A. Murthy, and A. Weiss, “Metalloproteinases and their natural inhibitors in inflammation and immunity,” Nature Reviews Immunology, vol. 13, no. 9, pp. 649–665, 2013. View at Publisher · View at Google Scholar · View at Scopus
  57. G. Murphy, A. Murthy, and R. Khokha, “Clipping, shedding and RIPping keep immunity on cue,” Trends in Immunology, vol. 29, no. 2, pp. 75–82, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. J. Müllberg, W. Oberthür, F. Lottspeich et al., “The soluble human IL-6 receptor. Mutational characterization of the proteolytic cleavage site,” The Journal of Immunology, vol. 152, no. 10, pp. 4958–4968, 1994. View at Google Scholar · View at Scopus
  59. C. K. Goth, A. Halim, S. A. Khetarpal, D. J. Rader, H. Clausen, and K. T.-B. G. Schjoldager, “A systematic study of modulation of ADAM-mediated ectodomain shedding by site-specific O-glycosylation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 47, pp. 14623–14628, 2015. View at Publisher · View at Google Scholar · View at Scopus
  60. N. D. Rawlings, M. Waller, A. J. Barrett, and A. Bateman, “MEROPS: the database of proteolytic enzymes, their substrates and inhibitors,” Nucleic Acids Research, vol. 42, no. 1, pp. D503–D509, 2014. View at Publisher · View at Google Scholar · View at Scopus
  61. J. Tucher, D. Linke, T. Koudelka et al., “LC-MS based cleavage site profiling of the proteases ADAM10 and ADAM17 using proteome-derived peptide libraries,” Journal of Proteome Research, vol. 13, no. 4, pp. 2205–2214, 2014. View at Publisher · View at Google Scholar · View at Scopus
  62. S. Riethmueller, J. C. Ehlers, J. Lokau et al., “Cleavage site localization differentially controls interleukin-6 receptor proteolysis by ADAM10 and ADAM17,” Scientific Reports, vol. 6, Article ID 25550, 2016. View at Publisher · View at Google Scholar
  63. J. C. Galicia, H. Tai, Y. Komatsu, Y. Shimada, K. Akazawa, and H. Yoshie, “Polymorphisms in the IL-6 receptor (IL-6R) gene: strong evidence that serum levels of soluble IL-6R are genetically influenced,” Genes and Immunity, vol. 5, no. 6, pp. 513–516, 2004. View at Publisher · View at Google Scholar · View at Scopus
  64. S. Rafiq, T. M. Frayling, A. Murray 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 & Immunity, vol. 8, no. 7, pp. 552–559, 2007. View at Publisher · View at Google Scholar · View at Scopus
  65. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium, “The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis,” The Lancet, vol. 379, no. 9822, pp. 1214–1224, 2012. View at Publisher · View at Google Scholar · View at Scopus
  66. N. Sarwar and A. S. Butterworth, “Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies,” The Lancet, vol. 379, no. 9822, pp. 1205–1213, 2012. View at Publisher · View at Google Scholar · View at Scopus
  67. R. C. Ferreira, D. F. Freitag, A. J. Cutler et al., “Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases,” PLoS Genetics, vol. 9, no. 4, Article ID e1003444, 2013. View at Publisher · View at Google Scholar · View at Scopus
  68. O. W. Stephens, Q. Zhang, P. Qu 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, vol. 119, no. 2, pp. 503–512, 2012. View at Publisher · View at Google Scholar · View at Scopus
  69. S. Horiuchi, W. Ampofo, Y. Koyanagi et al., “High-level production of alternatively spliced soluble interleukin-6 receptor in serum of patients with adult T-cell leukaemia/HTLV-I-associated myelopathy,” Immunology, vol. 95, no. 3, pp. 360–369, 1998. View at Publisher · View at Google Scholar · View at Scopus
  70. S. Dimitrov, T. Lange, C. Benedict et al., “Sleep enhances IL-6 trans-signaling in humans,” The FASEB Journal, vol. 20, no. 12, pp. 2174–2176, 2006. View at Publisher · View at Google Scholar · View at Scopus
  71. M. Leggate, M. A. Nowell, S. A. Jones, and M. A. Nimmo, “The response of interleukin-6 and soluble interleukin-6 receptor isoforms following intermittent high intensity and continuous moderate intensity cycling,” Cell Stress and Chaperones, vol. 15, no. 6, pp. 827–833, 2010. View at Publisher · View at Google Scholar · View at Scopus
  72. C. Garbers, N. Monhasery, S. Aparicio-Siegmund et al., “The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease, vol. 1842, no. 9, pp. 1485–1494, 2014. View at Publisher · View at Google Scholar · View at Scopus
  73. J. Wolf, S. Rose-John, and C. Garbers, “Interleukin-6 and its receptors: a highly regulated and dynamic system,” Cytokine, vol. 70, no. 1, pp. 11–20, 2014. View at Publisher · View at Google Scholar · View at Scopus
  74. S. Rose-John, H. Schooltink, D. Lenz et al., “Studies on the structure and regulation of the human hepatic interleukin-6 receptor,” European Journal of Biochemistry, vol. 190, no. 1, pp. 79–83, 1990. View at Publisher · View at Google Scholar · View at Scopus
  75. C. Garbers, F. Kuck, S. Aparicio-Siegmund et al., “Cellular senescence or EGFR signaling induces Interleukin 6 (IL-6) receptor expression controlled by mammalian target of rapamycin (mTOR),” Cell Cycle, vol. 12, no. 21, pp. 3421–3432, 2013. View at Publisher · View at Google Scholar · View at Scopus
  76. V. Matthews, B. Schuster, S. Schütze et al., “Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE),” The Journal of Biological Chemistry, vol. 278, no. 40, pp. 38829–38839, 2003. View at Publisher · View at Google Scholar · View at Scopus
  77. C. Garbers, N. Jänner, A. Chalaris 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,” The Journal of Biological Chemistry, vol. 286, no. 17, pp. 14804–14811, 2011. View at Publisher · View at Google Scholar · View at Scopus
  78. S. A. Jones, S. Horiuchi, D. Novick, N. Yamamoto, and G. M. Fuller, “Shedding of the soluble IL-6 receptor is triggered by Ca2+ mobilization, while basal release is predominantly the product of differential mRNA splicing in THP-1 cells,” European Journal of Immunology, vol. 28, no. 11, pp. 3514–3522, 1998. View at Google Scholar · View at Scopus
  79. E. M. Briso, O. Dienz, and M. Rincon, “Cutting edge: soluble IL-6R is produced by IL-6R ectodomain shedding in activated CD4 T cells,” The Journal of Immunology, vol. 180, no. 11, pp. 7102–7106, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. S. A. Jones, D. Novick, S. Horiuchi, N. Yamamoto, A. J. Szalai, and G. M. Fuller, “C-reactive protein: a physiological activator of interleukin 6 receptor shedding,” The Journal of Experimental Medicine, vol. 189, no. 3, pp. 599–604, 1999. View at Publisher · View at Google Scholar · View at Scopus
  81. N. Franchimont, C. Lambert, P. Huynen et al., “Interleukin-6 receptor shedding is enhanced by interleukin-1β and tumor necrosis factor α and is partially mediated by tumor necrosis factor α-converting enzyme in osteoblast-like cells,” Arthritis & Rheumatism, vol. 52, no. 1, pp. 84–93, 2005. View at Publisher · View at Google Scholar · View at Scopus
  82. N. Schumacher, D. Meyer, A. Mauermann et al., “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,” The Journal of Biological Chemistry, vol. 290, no. 43, pp. 26059–26071, 2015. View at Publisher · View at Google Scholar · View at Scopus
  83. I. Yan, J. Schwarz, K. Lücke et al., “ADAM17 controls IL-6 signaling by cleavage of the murine IL-6Rα from the cell surface of leukocytes during inflammatory responses,” Journal of Leukocyte Biology, vol. 99, no. 5, pp. 749–760, 2016. View at Publisher · View at Google Scholar
  84. P. G. Arndt, B. Strahan, Y. Wang, C. Long, K. Horiuchi, and B. Walcheck, “Leukocyte adam17 regulates acute pulmonary inflammation,” PLoS ONE, vol. 6, no. 5, Article ID e19938, 2011. View at Publisher · View at Google Scholar · View at Scopus
  85. L. Robb, D. J. Hilton, T. A. Willson, and C. Glenn Begley, “Structural analysis of the gene encoding the murine interleukin-11 receptor α-chain and a related locus,” The Journal of Biological Chemistry, vol. 271, no. 23, pp. 13754–13761, 1996. View at Publisher · View at Google Scholar · View at Scopus
  86. I. Tacken, Struktur- und Funktionsuntersuchungen am humanen Interleukin-11-Rezeptorkomplex [Ph.D. thesis], RWTH Aachen University, Aachen, Germany, 2002.
  87. C. T. N. Pham, “Neutrophil serine proteases: specific regulators of inflammation,” Nature Reviews Immunology, vol. 6, no. 7, pp. 541–550, 2006. View at Publisher · View at Google Scholar · View at Scopus
  88. B. Korkmaz, T. Moreau, and F. Gauthier, “Neutrophil elastase, proteinase 3 and cathepsin G: physicochemical properties, activity and physiopathological functions,” Biochimie, vol. 90, no. 2, pp. 227–242, 2008. View at Publisher · View at Google Scholar · View at Scopus
  89. V. Modur, Y. Li, G. A. Zimmerman, S. M. Prescott, and T. M. McIntyre, “Retrograde inflammatory signaling from neutrophils to endothelial cells by soluble interleukin-6 receptor alpha,” The Journal of Clinical Investigation, vol. 100, no. 11, pp. 2752–2756, 1997. View at Publisher · View at Google Scholar · View at Scopus
  90. U. Bank, D. Reinhold, C. Schneemilch, D. Kunz, H.-J. Synowitz, and S. Ansorge, “Selective proteolytic cleavage of IL-2 receptor and IL-6 receptor ligand binding chains by neutrophil-derived serine proteases at foci of inflammation,” Journal of Interferon and Cytokine Research, vol. 19, no. 11, pp. 1277–1287, 1999. View at Publisher · View at Google Scholar · View at Scopus
  91. E. P. McGreal, P. L. Davies, W. Powell et al., “Inactivation of IL-6 and soluble IL-6 receptor by neutrophil derived serine proteases in cystic fibrosis,” Biochimica et Biophysica Acta—Molecular Basis of Disease, vol. 1802, no. 7-8, pp. 649–658, 2010. View at Publisher · View at Google Scholar · View at Scopus
  92. C. Diveu, M. J. McGeachy, K. Boniface et al., “IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells,” The Journal of Immunology, vol. 182, no. 9, pp. 5748–5756, 2009. View at Publisher · View at Google Scholar · View at Scopus
  93. T. Robak, A. Gladalska, H. Stepień, and E. Robak, “Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis,” Mediators of Inflammation, vol. 7, no. 5, pp. 347–353, 1998. View at Publisher · View at Google Scholar · View at Scopus
  94. D. T. Teachey, S. F. Lacey, P. A. Shaw et al., “identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia,” Cancer Discovery, vol. 6, no. 6, pp. 664–679, 2016. View at Publisher · View at Google Scholar
  95. M. Narazaki, K. Yasukawa, T. Saito et al., “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, vol. 82, no. 4, pp. 1120–1126, 1993. View at Google Scholar · View at Scopus
  96. C. Garbers, W. Thaiss, G. W. Jones et al., “Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor,” The Journal of Biological Chemistry, vol. 286, no. 50, pp. 42959–42970, 2011. View at Publisher · View at Google Scholar · View at Scopus
  97. B. Rabe, A. Chalaris, U. May et al., “Transgenic blockade of interleukin 6 transsignaling abrogates inflammation,” Blood, vol. 111, no. 3, pp. 1021–1028, 2008. View at Publisher · View at Google Scholar · View at Scopus
  98. G. D. Brooks, L. McLeod, S. Alhayyani et al., “IL6 Trans-signaling promotes KRAS-driven lung carcinogenesis,” Cancer Research, vol. 76, no. 4, pp. 866–876, 2016. View at Publisher · View at Google Scholar
  99. P. Birner, S. Heider, P. Petzelbauer et al., “Interleukin-6 receptor alpha blockade improves skin lesions in a murine model of systemic lupus erythematosus,” Experimental Dermatology, vol. 25, no. 4, pp. 305–310, 2016. View at Publisher · View at Google Scholar
  100. R. Holmer, G. H. Wätzig, S. Tiwari, S. Rose-John, and H. Kalthoff, “Interleukin-6 trans-signaling increases the expression of carcinoembryonic antigen-related cell adhesion molecules 5 and 6 in colorectal cancer cells,” BMC Cancer, vol. 15, article 975, 2015. View at Publisher · View at Google Scholar · View at Scopus
  101. M. Luig, M. A. Kluger, B. Goerke et al., “Inflammation-induced IL-6 functions as a natural brake on macrophages and limits GN,” Journal of the American Society of Nephrology, vol. 26, no. 7, pp. 1597–1607, 2015. View at Publisher · View at Google Scholar · View at Scopus
  102. G. S. Braun, Y. Nagayama, Y. Maruta et al., “IL-6 trans-signaling drives murine crescentic GN,” Journal of the American Society of Nephrology, vol. 27, no. 1, pp. 132–142, 2016. View at Publisher · View at Google Scholar · View at Scopus
  103. A. L. Winship, M. Van Sinderen, J. Donoghue, K. Rainczuk, and E. Dimitriadis, “Targeting interleukin-11 receptor—impairs human endometrial cancer cell proliferation and invasion in vitro and reduces tumor growth and metastasis in vivo,” Molecular Cancer Therapeutics, vol. 15, no. 4, pp. 720–730, 2016. View at Publisher · View at Google Scholar
  104. N. Underhill-Day, L. A. McGovern, N. Karpovich, H. J. Mardon, V. A. Barton, and J. K. Heath, “Functional characterization of W147A: a high-affinity interleukin-11 antagonist,” Endocrinology, vol. 144, no. 8, pp. 3406–3414, 2003. View at Publisher · View at Google Scholar · View at Scopus
  105. V. A. Barton, K. R. Hudson, and J. K. Heath, “Identification of three distinct receptor binding sites of murine interleukin-11,” The Journal of Biological Chemistry, vol. 274, no. 9, pp. 5755–5761, 1999. View at Publisher · View at Google Scholar · View at Scopus
  106. C. G. Lee, D. Hartl, H. Matsuura et al., “Endogenous IL-11 signaling is essential in Th2- and IL-13-induced inflammation and mucus production,” American Journal of Respiratory Cell and Molecular Biology, vol. 39, no. 6, pp. 739–746, 2008. View at Publisher · View at Google Scholar · View at Scopus
  107. G. H. Waetzig and S. Rose-John, “Hitting a complex target: an update on interleukin-6 trans-signalling,” Expert Opinion on Therapeutic Targets, vol. 16, no. 2, pp. 225–236, 2012. View at Publisher · View at Google Scholar · View at Scopus