C1 The role of gp130 signalling during liver regeneration, inflammation and tumour formation: therapeutic perspectives

C1_April 2014

Principal Investigators:

Dr. rer. nat. Dirk Schmidt-Arras
Biochemisches Institut
Christian-Albrechts-Universität zu Kiel
Olshausenstr. 40
24098 Kiel
Tel.: +49-431-880-7112
Fax: +49-431-880-5007
E-mail: darras@biochem.uni-kiel.de

Prof. Dr. rer. nat. Stefan Rose-John
Biochemisches Institut
Christian-Albrechts-Universität zu Kiel
Olshausenstr. 40
24098 Kiel
Tel.: +49-431-880-3336
Fax: +49-431-880-5007
E-mail: rosejohn@biochem.uni-kiel.de

C1_IL-6 trans-signaling
Figure 1: Possible involvement of IL-6 trans-signaling and ADAM proteases in the development of inflammation-related malignant liver lesions

Project description

On target cells Interleukin-6 (IL-6) binds to its membrane-bound receptor (IL-6R) and the signal-transducing subunit gp130/IL-6ST. The soluble IL-6 receptor (sIL-6R) can be liberated proteolytically mainly by the metalloprotease ADAM17. In complex with the sIL-6R, IL-6 can bind now to cells that express gp130 but not the membrane-bound IL-6R. This process has been termed IL-6 ‘trans-signaling’. IL-6 trans-signalling via gp130 has been shown to play a pivotal role in liver regeneration, but also inflammatory and tumorigenic processes. gp130 has been shown to be mutated in hepatocellular adenoma and carcinoma.

C01 in 60 SecondsVideoarchiv

C01 in 60 Seconds online seit 19.03.2019

During the first funding period we were able to show that oncogenic mutations in gp130 lead to an increased flexibility of the gp130 extracellular domain and in consequence to ligand-independent activation. We could furthermore reveal that gp130 mutants signal from intracellular compartments.

In the future we will analyse the detailed molecular basis of gp130 activation. We will furthermore compare the spatio-temporal regulation and signal quality between ligand-stimulated and constitutive active gp130. Using cell biological approaches and animal models we will analyse the physiological consequences of persistent hepatocellular gp130 trans-signalling in vitro and in vivo.

In previous work we could identify ADAM-proteases in cells of the tumour stroma and cells of the metastatic niche as major switches for the generation of lung metastasis. Based on these findings we will analyse if ADAM proteases also play a crucial role for the generation of malignant hepatic lesions and hence present a target for therapeutic intervention.

Related news:

Heink S, Yogev N, Garbers C, Herwerth M, Aly L, Gasperi C, Husterer V, Croxford AL, Möller-Hackbarth K, Bartsch HS, Sotlar K, Krebs S, Regen T, Blum H, Hemmer B, Misgeld T, Wunderlich TF, Hidalgo J, Oukka M, Rose-John S, Schmidt-Supprian M, Waisman A, Korn T

Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic T(H)17 cells
Nat Immunol. 2017 Jan;18(1):74-85. doi: 10.1038/ni.3632. Epub 2016 Nov 28

Bergmann J, Müller M, Baumann N, Reichert M, Heneweer C, Bolik J, Lücke K, Gruber S, Carambia A, Boretius S, Leuschner I, Becker T, Rabe B, Herkel J, Wunderlich FT, Mittrücker HW, Rose-John S, Schmidt-Arras D

IL-6 trans-signaling is essential for the development of hepatocellular carcinoma in mice

Hepatology. 2016 Oct 22. doi: 10.1002/hep.28874. [Epub ahead of print]

Müller M, Wetzel S, Köhn-Gaone J, Chalupsky K, Lüllmann-Rauch R, Barikbin R, Bergmann J, Wöhner B, Zbodakova O, Leuschner I, Martin G, Tiegs G, Rose-John S, Sedlacek R, Tirnitz-Parker JE, Saftig P, Schmidt-Arras D

A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis
Oncotarget. 2016 Apr 5;7(14):17431-41. doi: 10.18632/oncotarget.7836.

Schmidt-Arras D, Rose-John S

IL-6 pathway in the liver: from physiopathology to therapy
J Hepatol. 2016 Jun;64(6):1403-15. doi: 10.1016/j.jhep.2016.02.004. Epub 2016 Feb 8.

Yan I, Schwarz J, Lücke K, Schumacher N, Schumacher V, Schmidt S, Rabe B, Saftig P, Donners M, Rose-John S, Mittrücker HW, Chalaris A

ADAM17 controls IL-6 signaling by cleavage of the murine IL-6Rα from the cell surface of leukocytes during inflammatory responses
J Leukoc Biol. 2016 May;99(5):749-60. doi: 10.1189/jlb.3A0515-207R. Epub 2015 Nov 11.