The role of the Interleukin-6 receptor in liver damage and regeneration

• Applicant: Professor Dr. Jürgen Scheller
• Subject Area: Gastroenterology ; Immunology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 446322183

• Final Report Year: 2024

Final Report Abstract

The interplay between the immune response and liver damage/regeneration is controlled by the interleukin (IL)-6 family of cytokines. IL-6 is directly involved in liver regeneration. To signal, IL-6 bind to the non-signal transducing IL-6 receptor (IL-6R) followed by Director complex formation with the signal transducing glycoprotein 130 (gp130) receptor. IL-6 deficient mice show a decelerated liver regeneration Carmen Auweiler-Niesen accompanied by increased mortality following partial hepatectomy (PHX). Previously, we showed that IL-6 trans-signalling controls hepatocyte proliferation and thus liver regeneration after PHX via direct and indirect mechanisms. Here, we addressed three main objectives and 1. identified hepatocytes as main target cells for IL-6 type cytokines, 2. rescued the PHX regeneration defect of IL-6R deficient mice by IL-6 type cytokines and 3. showed that constitutive active gp130 signaling restricted to hepatocytes did not rescue the PHX regeneration defect of IL-6R deficient mice. Additionally, in co-operation with the local Düsseldorf group of Prof. E. Lammert we published in Nature Communication that the myeloid-derived growth factor (MYDGF) is a mechanically induced angiocrine signal that induces growth and protection of primary mouse and human hepatocytes.

Publications

• Exclusive inhibition of IL-6 trans-signaling by soluble gp130FlyRFc. Cytokine: X, 3(4), 100058.
  Berg, Anna F.; Ettich, Julia; Weitz, Hendrik T.; Krusche, Matthias; Floss, Doreen M.; Scheller, Jürgen & Moll, Jens M.
  
• Tryptophan (W) at position 37 of murine IL-12/IL-23 p40 is mandatory for binding to IL-12Rβ1 and subsequent signal transduction. Journal of Biological Chemistry, 297(5), 101295.
  Georgy, Jacqueline; Arlt, Yvonne; Moll, Jens M.; Ouzin, Meryem; Weitz, Hendrik T.; Gremer, Lothar; Willbold, Dieter; Grötzinger, Joachim; Thives-Kurenbach, Felix; Scheller, Jürgen & Floss, Doreen M.
  
• A Hybrid Soluble gp130/Spike-Nanobody Fusion Protein Simultaneously Blocks Interleukin-6 trans -Signaling and Cellular Infection with SARS-CoV-2. Journal of Virology, 96(4).
  Ettich, Julia; Werner, Julia; Weitz, Hendrik T.; Mueller, Eva; Schwarzer, Roland; Lang, Philipp A.; Scheller, Jürgen & Moll, Jens M.
  
• Bispecific soluble cytokine receptor-nanobody fusions inhibit Interleukin (IL-)6 trans-signaling and IL-12/23 or tumor necrosis factor (TNF) signaling. Journal of Biological Chemistry, 299(11), 105343.
  Gesiorowski, Annika; Ettich, Julia; Werner, Julia; Wittich, Christoph; Pieper, Stephan; Padrini, Giacomo; Behnke, Kristina; Floss, Doreen M.; Lang, Philipp A.; Moll, Jens M. & Scheller, Jürgen
  
• Constitutive Activation of gp130 in T Cells Results in Senescence and Premature Aging. The Journal of Immunology, 210(11), 1641-1652.
  Rafii, Puyan; Reusswig, Friedrich; Werner, Julia; Xu, Haifeng; Lang, Philpp A.; Rose-John, Stefan; Gorressen, Simone; Alter, Christina; Schrader, Jürgen; Herebian, Diran; Floss, Doreen M.; Elvers, Margitta; Piekorz, Roland P.; Scheller, Jürgen & Behnke, Kristina
  
• Cytokimera GIL-11 rescued IL-6R deficient mice from partial hepatectomy-induced death by signaling via non-natural gp130:LIFR:IL-11R complexes. Communications Biology, 6(1).
  Rafii, Puyan; Seibel, Christiane; Weitz, Hendrik T.; Ettich, Julia; Minafra, Anna Rita; Petzsch, Patrick; Lang, Alexander; Floss, Doreen M.; Behnke, Kristina; Köhrer, Karl; Moll, Jens M. & Scheller, Jürgen
  
• Exploring the landscape of synthetic IL‐6‐type cytokines. The FEBS Journal, 291(10), 2030-2050.
  Scheller, Jürgen; Ettich, Julia; Wittich, Christoph; Pudewell, Silke; Floss, Doreen M. & Rafii, Puyan
  
• Targeting IL-6 trans-signalling: past, present and future prospects. Nature Reviews Immunology, 23(10), 666-681.
  Rose-John, Stefan; Jenkins, Brendan J.; Garbers, Christoph; Moll, Jens M. & Scheller, Jürgen
  
• Engineered interleukin-6-derived cytokines recruit artificial receptor complexes and disclose CNTF signaling via the OSMR. Journal of Biological Chemistry, 300(5), 107251.
  Rafii, Puyan; Cruz, Patricia Rodrigues; Ettich, Julia; Seibel, Christiane; Padrini, Giacomo; Wittich, Christoph; Lang, Alexander; Petzsch, Patrick; Köhrer, Karl; Moll, Jens M.; Floss, Doreen M. & Scheller, Jürgen
  
• Identification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes. Nature Communications, 15(1).
  Große-Segerath, Linda; Follert, Paula; Behnke, Kristina; Ettich, Julia; Buschmann, Tobias; Kirschner, Philip; Hartwig, Sonja; Lehr, Stefan; Korf-Klingebiel, Mortimer; Eberhard, Daniel; Lehwald-Tywuschik, Nadja; Al-Hasani, Hadi; Knoefel, Wolfram Trudo; Heinrich, Stefan; Levkau, Bodo; Wollert, Kai C.; Scheller, Jürgen & Lammert, Eckhard
  
• Unpaired cysteine insertions favor transmembrane dimerization and induce ligand-independent constitutive cytokine receptor signaling. Biological Chemistry, 405(7-8), 531-544.
  Baumgärtner, Lynn Affrica Felicitas; Ettich, Julia; Balles, Helene; Lapp, Dorothee Johanna; Mossner, Sofie; Bassenge, Christin; Ouzin, Meryem; Hanenberg, Helmut; Scheller, Jürgen & Floss, Doreen Manuela