Hyper-IL-6

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Hyper-IL-6 is a designer cytokine, which was generated by the German biochemist Stefan Rose-John. [1] Hyper-IL-6 is a fusion protein of the four-helical cytokine Interleukin-6 and the soluble Interleukin-6 receptor which are covalently linked by a flexible peptide linker. [1] Interleukin-6 on target cells binds to a membrane bound Interleukin-6 receptor. [2] The complex of Interleukin-6 and the Interleukin-6 receptor associate with a second receptor protein called gp130, which dimerises and initiates intracellular signal transduction. [3] Gp130 is expressed on all cells of the human body whereas the Interleukin-6 receptor is only found on few cells such as hepatocytes and some leukocytes. [4] Neither Interleukin-6 nor the Interleukin-6 receptor have a measurable affinity for gp130. [5] Therefore, cells, which only express gp130 but no Interleukin-6 receptor are not responsive to Interleukin-6. [5] It was found, however, that the membrane-bound Interleukin-6 receptor can be cleaved from the cell membrane generating a soluble Interleukin-6 receptor. [6] The soluble Interleukin-6 receptor can bind the ligand Interleukin-6 with similar affinity as the membrane-bound Interleukin-6 receptor and the complex of Interleukin-6 and the soluble Interleukin-6 receptor can bind to gp130 on cells, which only express gp130 but no Interleukin-6 receptor. [7] The mode of signaling via the soluble Interleukin-6 receptor has been named Interleukin-6 trans-signaling whereas Interleukin-6 signaling via the membrane-bound Interleukin-6 receptor is referred to as Interleukin-6 classic signaling. [8] Therefore, the generation of the soluble Interleukin-6 receptor enables cells to respond to Interleukin-6, which in the absence of soluble Interleukin-6 receptor would be completely unresponsive to the cytokine. [8]

Contents

Molecular construction of Hyper-IL-6

In order to generate a molecular tool to discriminate between Interleukin-6 classic signaling and Interleukin-6 trans-signaling, a cDNA coding for human Interleukin-6 and a cDNA coding for the human soluble Interleukin-6 receptor were connected by a cDNA coding for a 13 amino acids long linker, which was long enough to bridge the 40 Å distance between the COOH terminus of the soluble Interleukin-6 receptor and the NH2 terminus of human Interleukin-6. [9] The generated cDNA was expressed in yeast cells and in mammalian cells and it was shown that. [10]

Hyper-IL-6.jpg

Use of Hyper-IL-6 to analyse IL-6 signaling

Hyper-IL-6 has been used to test which cells depend on Interleukin-6 trans-signaling in their response to the cytokine Interleukin-6. To this end, cells were treated with Interleukin-6 and alternatively with Hyper-IL-6. Cells, which respond to Interleukin-6 alone do express an Interleukin-6 receptor whereas cells, which only respond to Hyper-IL-6 but not to Interleukin-6 alone depend in their response to the cytokine on Interleukin-6 trans-signaling. [11] It turned out that hematopoietic stem cells, [12] neural cells, [13] smooth muscle cells [14] and endothelial cells [15] are typical target cells of Interleukin-6 trans-signaling.

The concept of Interleukin-6 trans-signaling

The Hyper-IL-6 protein has also been used to explore the physiologic role of Interleukin-6 trans-signaling in vivo. It turned out that this signaling mode was involved in many types of inflammation [16] and cancer. [17]

Hyper-IL-6 has helped to establish the concept of Interleukin-6 trans-signaling. [18] Interleukin-6 trans-signaling mediates the pro-inflammatory activities of Interleukin-6 whereas Interleukin-6 classic signaling governs the protective and regenerative Interleukin-6 activities. [19] Recently, in breast cancer patients, it was shown with the help of Hyper-IL-6 that IL-6 trans-signaling via phosphoinositid-3-kinase signaling activates disseminated cancer cells long before metastases are formed. [20] In addition, it was demonstrated in mice that Hyper-IL-6 transneuronal delivery enabled functional recovery after severe spinal cord injury. [21]

References

  1. 1 2 Fischer, Martina; Goldschmitt, Jutta; Peschel, Christian; Brakenhoff, Just P. G.; Kallen, Karl-Josef; Wollmer, Axel; Grötzinger, Joachim; Rose-John, Stefan (February 1997). "A bioactive designer cytokine for human hematopoietic progenitor cell expansion". Nature Biotechnology. 15 (2): 142–145. doi:10.1038/nbt0297-142. PMID   9035138. S2CID   22721071.
  2. ↑ Jones, Simon A.; Jenkins, Brendan J. (25 September 2018). "Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer" (PDF). Nature Reviews Immunology. 18 (12): 773–789. doi:10.1038/s41577-018-0066-7. PMID   30254251. S2CID   52823385.
  3. ↑ Schaper, Fred; Rose-John, Stefan (October 2015). "Interleukin-6: Biology, signaling and strategies of blockade". Cytokine & Growth Factor Reviews. 26 (5): 475–487. doi:10.1016/j.cytogfr.2015.07.004. PMID   26189695.
  4. ↑ Taga, Tetsuya; Kishimoto, Tadamitsu (April 1997). "Gp130 and the interleukin-6 Family of Cytokines". Annual Review of Immunology. 15 (1): 797–819. doi:10.1146/annurev.immunol.15.1.797. PMID   9143707.
  5. 1 2 Rose-John, Stefan (2012). "IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6". International Journal of Biological Sciences. 8 (9): 1237–1247. doi:10.7150/ijbs.4989. PMC   3491447 . PMID   23136552.
  6. ↑ Mülberg, Jürgen; Schooltink, Heidi; Stoyan, Tanja; Günther, Monika; Graeve, Lutz; Buse, Gerhard; Mackiewicz, Andrzej; Heinrich, Peter C.; Rose-John, Stefan (February 1993). "The soluble interleukin-6 receptor is generated by shedding". European Journal of Immunology. 23 (2): 473–480. doi:10.1002/eji.1830230226. PMID   8436181. S2CID   22834660.
  7. ↑ Mackiewicz, A.; Schooltink, H.; Heinrich, P. C.; Rose-John, S. (15 September 1992). "Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins". The Journal of Immunology. 149 (6): 2021–2027. doi:10.4049/jimmunol.149.6.2021. PMID   1381393.
  8. 1 2 Rose-John, S; Heinrich, P C (1 June 1994). "Soluble receptors for cytokines and growth factors: generation and biological function". Biochemical Journal. 300 (2): 281–290. doi:10.1042/bj3000281. PMC   1138158 . PMID   8002928.
  9. ↑ Grotzinger, Joachim; Kurapkat, Günther; Wollmer, Axel; Kalai, Michael; Rose-John, Stefan (January 1997). "The family of the IL-6-Type cytokines: Specificity and promiscuity of the receptor complexes". Proteins: Structure, Function, and Genetics. 27 (1): 96–109. doi:10.1002/(SICI)1097-0134(199701)27:1<96::AID-PROT10>3.0.CO;2-D. PMID   9037715. S2CID   35512559.
  10. ↑ Peters, Malte; Müller, Albrecht M.; Rose-John, Stefan (15 November 1998). "Interleukin-6 and Soluble Interleukin-6 Receptor: Direct Stimulation of gp130 and Hematopoiesis". Blood. 92 (10): 3495–3504. doi:10.1182/blood.V92.10.3495. PMID   9808540.
  11. ↑ Wolf, Janina; Rose-John, Stefan; Garbers, Christoph (November 2014). "Interleukin-6 and its receptors: A highly regulated and dynamic system". Cytokine. 70 (1): 11–20. doi:10.1016/j.cyto.2014.05.024. PMID   24986424.
  12. ↑ Audet, Julie; Miller, Cindy L.; Rose-John, Stefan; Piret, James M.; Eaves, Connie J. (13 February 2001). "Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells". Proceedings of the National Academy of Sciences of the United States of America. 98 (4): 1757–1762. Bibcode:2001PNAS...98.1757A. doi: 10.1073/pnas.98.4.1757 . JSTOR   3054949. PMC   29330 . PMID   11172024.
  13. ↑ März, Pia; Cheng, Jr-Gang; Gadient, Reto A.; Patterson, Paul H.; Stoyan, Tanja; Otten, Uwe; Rose-John, Stefan (17 March 1998). "Sympathetic neurons can produce and respond to interleukin 6". Proceedings of the National Academy of Sciences of the United States of America. 95 (6): 3251–3256. Bibcode:1998PNAS...95.3251M. doi: 10.1073/pnas.95.6.3251 . JSTOR   44831. PMC   19728 . PMID   9501249.
  14. ↑ Klouche, Mariam; Bhakdi, Sucharit; Hemmes, Monika; Rose-John, Stefan (15 October 1999). "Novel Path to Activation of Vascular Smooth Muscle Cells: Up-Regulation of gp130 Creates an Autocrine Activation Loop by IL-6 and Its Soluble Receptor" . The Journal of Immunology. 163 (8): 4583–4589. doi:10.4049/jimmunol.163.8.4583. PMID   10510402.
  15. ↑ Romano, Maria; Sironi, Marina; Toniatti, Carlo; Polentarutti, Nadia; Fruscella, Paolo; Ghezzi, Pietro; Faggioni, Raffaella; Luini, Walter; van Hinsbergh, Victor; Sozzani, Silvano; Bussolino, Federico; Poli, Valeria; Ciliberto, Gennaro; Mantovani, Alberto (March 1997). "Role of IL-6 and Its Soluble Receptor in Induction of Chemokines and Leukocyte Recruitment". Immunity. 6 (3): 315–325. doi: 10.1016/s1074-7613(00)80334-9 . PMID   9075932.
  16. ↑ Calabrese, Leonard H.; Rose-John, Stefan (19 August 2014). "IL-6 biology: implications for clinical targeting in rheumatic disease". Nature Reviews Rheumatology. 10 (12): 720–727. doi: 10.1038/nrrheum.2014.127 . PMID   25136784. S2CID   31635688.
  17. ↑ Schmidt, Stefanie; Schumacher, Neele; Schwarz, Jeanette; Tangermann, Simone; Kenner, Lukas; Schlederer, Michaela; Sibilia, Maria; Linder, Markus; Altendorf-Hofmann, Annelore; Knösel, Thomas; Gruber, Elisabeth S.; Oberhuber, Georg; Bolik, Julia; Rehman, Ateequr; Sinha, Anupam; Lokau, Juliane; Arnold, Philipp; Cabron, Anne-Sophie; Zunke, Friederike; Becker-Pauly, Christoph; Preaudet, Adele; Nguyen, Paul; Huynh, Jennifer; Afshar-Sterle, Shoukat; Chand, Ashwini L.; Westermann, Jürgen; Dempsey, Peter J.; Garbers, Christoph; Schmidt-Arras, Dirk; Rosenstiel, Philip; Putoczki, Tracy; Ernst, Matthias; Rose-John, Stefan (2 April 2018). "ADAM17 is required for EGF-R–induced intestinal tumors via IL-6 trans-signaling". Journal of Experimental Medicine. 215 (4): 1205–1225. doi:10.1084/jem.20171696. PMC   5881468 . PMID   29472497.
  18. ↑ Rose-John, Stefan; Winthrop, Kevin; Calabrese, Leonard (15 June 2017). "The role of IL-6 in host defence against infections: immunobiology and clinical implications". Nature Reviews Rheumatology. 13 (7): 399–409. doi:10.1038/nrrheum.2017.83. PMID   28615731. S2CID   205519501.
  19. ↑ Garbers, Christoph; Heink, Sylvia; Korn, Thomas; Rose-John, Stefan (4 May 2018). "Interleukin-6: designing specific therapeutics for a complex cytokine". Nature Reviews Drug Discovery. 17 (6): 395–412. doi:10.1038/nrd.2018.45. PMID   29725131. S2CID   19238101.
  20. ↑ Werner-Klein M, Grujovic A, Irlbeck C, Obradović M, Hoffmann M, Koerkel-Qu H, Lu X, Treitschke S, Köstler C, Botteron C, Weidele K, Werno C, Polzer B, Kirsch S, Gužvić M, Warfsmann J, Honarnejad K, Czyz Z, Feliciello G, Blochberger I, Grunewald S, Schneider E, Haunschild G, Patwary N, Guetter S, Huber S, Rack B, Harbeck N, Buchholz S, Rümmele P, Heine N, Rose-John S, Klein CA (2020) Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency. Nat Commun 11(1):4977
  21. ↑ Leibinger M, Zeitler C, Gobrecht P, Anastasia Andreadaki A, Gisselmann G, Fischer D (2021) Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice. Nat Commun 12(1):391
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