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The role of IL-6 trans-siganling in inflammation and cancer


Interleukin-6 (IL-6) mediated signals are important for the coordination of the immune system and IL-6 dysregulation can lead to chronic inflammation and cancer development. The trans-membrane proteins gp130 and Interleukin-6 receptor (IL-6R) constitute the signal transducing complex after IL-6 stimulation (IL-6 classic signaling). The agonistic soluble IL-6R (sIL-6R) in complex with IL-6 can stimulate cells only expressing gp130 on their surface. This process is called IL-6 trans-signaling. Since most somatic cells do not express the membrane-bound, cellular IL-6R, most cells are normally not responsive to IL-6 alone. IL-6 binds to the cellular IL-6R, whereas IL-6 alone has no measurable affinity to gp130. IL-6 bind to sIL-6R with the same affinity as to cellular IL-6R. The complex composed of IL-6 and sIL-6R can bind to gp130 and induce signal transduction. Accordingly, naturally occurring soluble gp130 (sgp130) was found in human and murine serum and can form complexes with IL-6 and sIL-6R but does not bind to IL-6 and cellular IL-6R alone. As the IL-6/sIL-6R complex binds equally well to membrane-bound and soluble gp130, a molar excess of sgp130 completely blocks trans-signaling responses but not IL-6 classic signalling. IL-6 trans-signaling is important for the regulation of cellular differentiation and apoptosis, and has direct consequences on acute and chronic inflammation and on tumor development.


Publications 2008-2011

1.    Suthaus, J., Adam, N., Grötzinger, J., Scheller, J., and Rose-John, S. (2011) Viral Interleukin-6: Structure, pathophysiology and strategies of neutralization, Eur J Cell Biol Epub.
2.    Scheller, J., Chalaris, A., Schmidt-Arras, D., and Rose-John, S. (2011) The pro- and anti-inflammatory properties of the Cytokine Interleukin-6, Biochim Biophys Acta - Mol Cell Res 1813, 878-888.
3.    Scheller, J., Chalaris, A., Garbers, C., and Rose-John, S. (2011) ADAM17: a masterswitch of inflammatory and regenerative responses?, Trends Immunol in press.
4.    Scheller, J., Chalaris, A., Garbers, C., and Rose-John, S. (2011) ADAM17: a molecular switch controlling inflammatory and regenerative responses, Trends Immunol in press.
5.    Nechemia-Arbely, Y., Shriki, A., Denz, U., Drucker, C., Scheller, J., Raub, J., Pappo, O., Rose-John, S., Galun, E., and Axelrod, J. H. (2011) Early hepatocyte DNA synthetic response posthepatectomy is modulated by IL-6 trans-signaling and PI3K/AKT activation, J Hepatol 54, 922-929.
6.    Malchow, S., Thaiss, W., Jänner, N., Waetzig, G. H., Gewiese-Rabsch, J., Garbers, C., Yamamoto, K., Rose-John, S., and Scheller, J. (2011) Essential role of neutrophil mobilization in concanavalin A-induced hepatitis is based on classic IL-6 signaling but not on IL-6 trans-signaling, Biochim Biophys Acta 1812, 290-301.
7.    Kruglov, A. A., Tumanov, A. V., Grivennikov, S. I., Shebzukhov, Y. V., Kuchmiy, A. A., Efimov, G. A., Drutskaya, M. S., Scheller, J., Kuprash, D. V., and Nedospasov, S. A. (2011) Modalities of Experimental TNF Blockade In Vivo: Mouse Models, Adv Exp Med Biol 691, 421-431.
8.    Garbers, C., Jänner, N., Chalaris, A., Moss, M. L., Floss, D. M., Meyer, D., Koch-Nolte, F., Rose-John, S., and Scheller, J. (2011) Species specificity of ADAM10 and ADAM7 in IL-6 transsignaling and novel role of ADAM10 in inducible IL-6R shedding, J Biol Chem 286, 14804-14811.
9.    Chalaris, A., Garbers, C., Rabe, B., Rose-John, S., and Scheller, J. (2011) The soluble Interleukin 6 receptor: Generation and role in inflammation and cancer, Eur J Cell Biol Epub ahead of print doi:10.1016/j.ejcb.2010.10.007.
10.    Barkhausen, T., Tschernig, T., Rosenstiel, P., van Griensven, M., Vonberg, R. P., Dorsch, M., Mueller-Heine, A., Chalaris, A., Scheller, J., Rose-John, S., Seegert, D., Krettek, C., and Waetzig, G. H. (2011) Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model, Crit Care Med Epub ahead of print.
11.    Waetzig, G. H., Chalaris, A., Rosenstiel, P., Suthaus, J., Holland, C., Karl, N., Uriarte, L. V., Till, A., Scheller, J., Grötzinger, J., Schreiber, S., Rose-John, S., and Seegert, D. (2010) N-linked glycosylation is essential for the stability, but not the function of the interleukin-6 signal transducer gp130, J Biol Chem 285, 1781-1789.
12.    Suthaus, J., Tillmann, A., Lorenzen, I., Bulanova, E., Rose-John, S., and Scheller, J. (2010) Forced homo- and heterodimerization of all gp130-type receptor complexes leads to constitutive ligand-independent signaling and cytokine-independent growth, Mol Biol Cell 21, 2797-2807.
13.    Rodriguez, N., Dietrich, H., Mossbrugger, I., Weintz, G., Scheller, J., Hammer, M., Quintanilla-Martinez, L., Rose-John, S., Miethke, T., and Lang, R. (2010) Increased inflammation and impaired resistance to Chlamydophila pneumoniae infection in Dusp1(-/-) mice: critical role of IL-6, J Leukoc Biol 88, 579-587.
14.    Matsumoto, S., Hara, T., Mitsuyama, K., Yamamoto, M., Tsuruta, O., Sata, M., Scheller, J., Rose-John, S., Kado, S., and Takada, T. (2010) Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model, J Immunol 184, 1543-1551.
15.    Larsen, J. V., Hansen, M., Møller, B., Madsen, P., Scheller, J., Nielsen, M., and Petersen, C. M. (2010) Sortilin facilitates signaling of ciliary neurotrophic factor and related helical type 1 cytokines targeting the gp130/leukemia inhibitory factor receptor beta heterodimer, Mol Cell Biol 30, 4175-4187.
16.    Jones, G. W., McLoughlin, R. M., Hammond, V. J., Parker, C. R., Williams, J. D., Malhotra, R., Scheller, J., Williams, A. S., Rose-John, S., Topley, N., and Jones, S. A. (2010) Loss of CD4 T cell IL-6R expression during inflammation underlines a role for IL-6 trans-signaling in the local maintenance of Th17 cells, J Immunol 184, 2130-2139.
17.    Giersberg, M., Floss, D., Kiprijanov, S., Conrad, U., and Scheller, J. (2010) Covalent dimerization between a camelidae anti-human TNF single domain antibody and the constant kappa light chain domain improves neutralizing capacity, Biotechnol Bioeng 106, 161-166.
18.    Gewiese-Rabsch, J., Drucker, C., Malchow, S., Scheller, J., and Rose-John, S. (2010) Role of IL-6 trans-signaling in CCl4induced liver damage, Biochim Biophys Acta 1802, 1054-1061.
19.    Drucker, C., Gewiese, J., Malchow, S., Scheller, J., and Rose-John, S. (2010) Impact of interleukin-6 classic- and trans-signaling on liver damage and regeneration, J Autoimmun 34, 29-37.
20.    Conrad, U., Plagmann, I., Malchow, S., Sack, M., Floss, D. M., Kruglov, A. A., Nedospasov, S. A., Rose-John, S., and Scheller, J. (2010) ELPylated anti-human TNF therapeutic single-domain antibodies for prevention of lethal septic shock, Plant Biotechnol J 9, 22-31.
21.    Chalaris, A., Gewiese, J., Fleig, L., Schneede, A., Rose-John, S., and Scheller, J. (2010) ADAM17-mediated shedding of the IL6R induces cleavage of the membrane stub by ?-secretase, BBA - Molecular Cell Research 1803, 234-245.
22.    Chalaris, A., Adam, N., Sina, C., Rosenstiel, P., Paliga, K., Lehmann, J., Schirmacher, P., Hartmann, D., Cichy, J., Gavrilowa, O., Schreiber, S., Jostock, T., Matthews, V., Häsler, R., Becker, C., Neurath, M. F., Reiß, K., Scheller, J., and Rose-John, S. (2010) Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice, J Exp Med 207, 1617-1624.
23.    Bender, M., Hofmann, S., Stegner, D., Chalaris, A., Bösl, M., Braun, A., Scheller, J., Rose-John, S., and Nieswandt, B. (2010) Differentially regulated GPVI ectodomain shedding by multiple platelet-expressed proteinases, Blood 116, 3347-3355.
24.    Sina, C., Förster, M., Derer, S., Hildebrand, F., Chalaris, A., Rabe, B., Scheller, J., Gavrilowa, O., Rehmann, A., Ott, S., Häsler, R., Li, J., Nikolaus, S., Fölsch, U. R., Rose-John, S., Schreiber, S., and Rosenstiel, P. (2009) G-protein coupled receptor 43 (GPR43) is essential for neutrophil recruitment during intestinal inflammation, J Immunol 183, 7514-7522.
25.    Rose-John, S., Mitsuyama, K., Matsumoto, S., Thaiss, W. M., and Scheller, J. (2009) Interleukin-6 trans-signaling and colonic cancer associated with inflammatory bowel disease, Curr Pharm Des 15, 2095-2103.
26.    Prakash, R., Satory, D., Dray, E., Papusha, A., Scheller, J., Kramer, W., Krejci, L., Klein, H., Haber, J. E., Sung, P., and Ira, G. (2009) Yeast Mph1 helicase dissociates Rad51-made D-loops: implications for crossover control in mitotic recombination, Genes Dev 23, 67-79.
27.    Plagmann, I., Chalaris, A., Nedospasov, S., Posenstiel, P., Rose-John, S., and Scheller, J. (2009) Transglutaminase-catalyzed covalent multimerization of camelidae anti-human TNFa single domain antibodies improves neutralizing capacity of human TNFa, J Biotechnol 142, 170-178.
28.    Nowell, M. A., Williams, A. S., Carty, S. A., Scheller, J., Hayes, A. J., Jones, G. W., Richards, P. J., Slinn, S., Ernst, M., Jenkins, B. J., Topley, N., Rose-John, S., and Jones, S. A. (2009) Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis, J Immunol 182, 613-622.
29.    May, U., Schiffelholz, T., Baier, P. C., Krueger, J. M., Rose-John, S., and Scheller, J. (2009) IL6-trans-signalling increases rapid-eye-movement sleep in rats, EJP 613, 141-145.
30.    Grivennikov, S., Karin, E., Teric, J., Mucida, D., Yu, G. Y., Vallabhapurapu, S., Scheller, J., Rose-John, S., Cheroutre, H., Eckmann, L., and Karin, M. (2009) IL-6 and STAT3 are required for survival of intestinal epithelial cells and development of colitis associated cancer, Cancer Cell 15, 103-113.
31.    Floss, D. M., Schallau, K., Rose-John, S., Conrad, U., and Scheller, J. (2009) Elastin-like polypeptides revolutionize recombinant protein expression and their medical application, Trends Biotechnol 28, 37-45.
32.    Floss, D., Sack, M., Acalis, E., Stadlmann, J., Quendler, H., Rademacher, T., Stoger, E., Scheller, J., Fischer, R., and Conrad, U. (2009) Influence of Elastin-like Peptide Fusion on Quantity and Quality of a Tobacco-produced Anti HIV Antibody, Plant Biotechnol J 7, 899-913.
33.    Drucker, C., Rabe, B., Chalaris, A., Schulz, E., Scheller, J., and Rose-John, S. (2009) Interleukin-6 Trans-Signaling Regulates Glycogen Consumption After d-Galactosamine-Induced Liver Damage, J Interferon Cytokine Res 29, 711-717.
34.    Benedict, C., Scheller, J., Rose-John, S., Born, J., and Marshall, L. (2009) Enhancing influence of intranasal interleukin-6 on slow wave activity and memory consolidation during sleep, FASEB J 23, 3629-3636.
35.    Baier, P. C., May, U., Scheller, J., Rose-John, S., and Schiffelholz, T. (2009) Impaired hippocampus-dependent and independent learning in IL-6 deficient mice, Behav Brain Res 613, 141-145.
36.    Adam, N., Rabe, B., Suthaus, J., Grötzinger, J., Rose-John, S., and Scheller, J. (2009) Unraveling Viral Interleukin 6 binding to gp130 and activation of STAT-Signaling Pathways independent of Interleukin 6-Receptor, J Virol 83, 5117-5126.
37.    West, M. A., Prescott, A. R., Chan, K. M., Zhou, Z., Rose-John, S., Scheller, J., and Watts, C. (2008) TLR-ligand induced podosome disassembly is ADAM17 dependent in dendritic cells and is accompanied by transient loss of migratory capacity, J Cell Biol 182, 993-1005.
38.    Tenhumberg, S., Waetzing, G. H., Chalaris, A., Rabe, B., Seegert, D., Scheller, J., Rose-John, S., and Grötzinger, J. (2008) Structure guided optimization of the Interleukin-6 Transsignaling antagonist sgp130, J Biol Chem 283, 27200-27207.
39.    Sudarman, E., Bollati-Fogolin, M., Hafner, M., Müller, W., Scheller, J., Rose-John, S., and Eichler, J. (2008) Synthetic Mimetics of the gp130 binding site for viral Interleukin 6 as inhibitors of the vIL6-gp130 interaction, Chem Biol Drud Des 71, 494-500.
40.    Rabe, B., Chalaris, A., May, U., Waetzig, G. H., Seegert, D., Williams, A. S., Jones, S. A., Rose-John, S., and Scheller, J. (2008) Transgenic blockade of interleukin 6 transsignaling abrogates inflammation, Blood 111, 1021-1028.
41.    Marino, M., Scuderi, F., Provenzano, C., Scheller, J., Rose-John, S., and Bartoccioni, E. (2008) IL-6 regulates MCP-1, ICAM and IL6-expression in human myoblasts, J Neuroimmunol 196, 41-48.
42.    Floss, D., Sack, M., Stadlmann, J., Rademacher, T., Scheller, J., Stöger, E., Fischer, R., and Conrad, U. (2008) Biochemical and functional characterization of anti-HIV antibody ELP fusion proteins from transgenic plants, Plant Biotechnol J 6, 379-391.
43.    Benrick, A., Jirholt, P., Wernstedt, I., Gustafsson, M., Scheller, J., Eriksson, A. L., Borén, J., Hedner, T., Ohlsson, C., Härd, T., Rose-John, S., and Jansson, J. O. (2008) A non-conservative polymorphism in the IL-6 signal transducer (IL6ST)/gp130 is associated with myocardial infarction in a hypertensive population, Regul Pept 146, 189-196.