title: Interleukin-6 trans-signaling and colonic cancer associated with inflammatory bowel disease.
abstract: Interleukin-6 (IL-6) is a cytokine largely induced during infection, inflammation, and cancer. In the liver, IL-6 induces the synthesis of acute-phase proteins, which are believed to support the response of the body during infection and inflammation. Moreover, IL-6 has been reported to be a growth factor in multiple myeloma. IL-6 on cells binds to an IL-6 receptor (IL-6R) forming an IL-6/IL-6R complex, which associates with a homodimer of a second receptor subunit, gp130, to initiate signaling. Gp130 is present on all cells of the body, whereas IL-6R is only expressed on hepatocytes, some leukocytes, and some epithelial cells. Since gp130 has no measurable affinity for IL-6, cells which do not express IL-6R are unresponsive to the cytokine. A soluble form of IL-6R, which is found in the blood, can still bind IL-6 and the complex of IL-6/sIL-6R can bind to cellular gp130 also on cells without IL-6R expression. This signaling mechanism has been called trans-signaling. Interestingly, a soluble form of gp130 (sgp130) blocks IL-6 trans-signaling without affecting classic IL-6 signaling via the membrane-bound IL-6R. We used a dimerized version of sgp130 fused to the Fc portion of an IgG1 antibody (sgp130Fc) to discriminate between classic and trans-signaling of IL-6. It turned out that proinflammatory activities of IL-6 are mediated via trans-signaling, whereas anti-inflammatory or regenerative activities are mediated via classic signaling. These results are important for strategies to inhibit IL-6 signaling in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and inflammation-associated colorectal cancer.
authors.affiliation: Institute of Biochemistry, Christian Albrechts University, Kiel, Germany.
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.forename: Dirk
authors.initials: D
authors.lastname: Schmidt-Arras
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000188:drug therapy; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy; D050822:Cytokine Receptor gp130 / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000276:immunology* / Q000628:therapy; D015850:Interleukin-6 / Q000819:agonists / Q000276:immunology*; D008113:Liver Neoplasms / Q000097:blood / Q000188:drug therapy; D051379:Mice; D008969:Molecular Sequence Data; D019947:Receptors, Interleukin-6 / Q000097:blood; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D015398:Signal Transduction; D000093242:Interleukin-6 Inhibitors
chemical_list: D050822:Cytokine Receptor gp130; D016207:Cytokines; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D000093242:Interleukin-6 Inhibitors; C519852:olamkicept