The IL-6/sIL-6R complex as a novel target for therapeutic approaches.
IL-6 plays a pivotal role in immune responses and certain oncologic conditions. The intense investigation of its biological activity and function led to the discovery of two different IL-6-driven signalling pathways. Binding to the membrane-bound IL-6 receptor (mIL-6R, CD126) causes the recruitment of two gp130 co-receptor molecules (CD130) and the activation of intracellular signalling cascades via gp130. Although this classical pathway is mainly limited to hepatocytes, neutrophils, monocytes/macrophages and certain other leukocyte populations, which express IL-6R on their surface, an alternative mechanism has also been described. Proteolytic cleavage of the mIL-6R protein or translation from alternatively spliced mRNA leads to the generation of a soluble form of the IL-6R (sIL-6R), which is likewise able to bind to IL-6. The resulting IL-6/sIL-6R complex is also capable of binding to gp130 and inducing intracellular signalling. Through this so-called 'trans-signalling' mechanism, IL-6 is able to stimulate cells that lack an endogenous mIL-6R. High levels of IL-6 and sIL-6R have been reported in several chronic inflammatory and autoimmune diseases as well as in cancer. Preclinical animal disease models have provided strong evidence that specific blockade of IL-6-regulated signalling pathways represents a promising approach for the therapy of these diseases. An optimised variant of the recently described fusion protein sgp30Fc is now heading towards its clinical evaluation.
Rose-John
Stefan
S
Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, Kiel, Germany. rosejohn@biochem.uni-kiel.de
Waetzig
Georg H
GH
Scheller
Jürgen
J
Grötzinger
Joachim
J
Seegert
Dirk
D
D017398:Alternative Splicing; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001168:Arthritis / Q000188:drug therapy; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001249:Asthma / Q000188:drug therapy; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000378:metabolism; D002460:Cell Line / Q000187:drug effects; D002986:Clinical Trials as Topic; D003092:Colitis / Q000188:drug therapy / Q000276:immunology; D003110:Colonic Neoplasms / Q000188:drug therapy; D050822:Cytokine Receptor gp130 / Q000502:physiology; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D015850:Interleukin-6 / Q000502:physiology; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D012995:Solubility; D016212:Transforming Growth Factor beta / Q000502:physiology; D000093242:Interleukin-6 Inhibitors
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D050822:Cytokine Receptor gp130; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; C494199:IL6ST protein, human; C104543:interleukin 6-interleukin 6 receptor fusion protein, recombinant; C519852:olamkicept