The IL-6/sIL-6R complex as a novel target for therapeutic approaches

Expert Opin Ther Targets. 2007 May;11(5):613-24. doi: 10.1517/14728222.11.5.613.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Alternative Splicing
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Arthritis / drug therapy
  • Arthritis, Rheumatoid / drug therapy
  • Asthma / drug therapy
  • Autoimmune Diseases / drug therapy*
  • Autoimmune Diseases / metabolism
  • Cell Line / drug effects
  • Clinical Trials as Topic
  • Colitis / drug therapy
  • Colitis / immunology
  • Colonic Neoplasms / drug therapy
  • Cytokine Receptor gp130 / physiology
  • Disease Models, Animal
  • Drug Delivery Systems
  • Drug Evaluation, Preclinical
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / metabolism
  • Interleukin-6 / antagonists & inhibitors*
  • Interleukin-6 / physiology
  • Leukocytes / metabolism
  • Male
  • Mice
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Receptors, Interleukin-6 / antagonists & inhibitors*
  • Receptors, Interleukin-6 / chemistry
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / physiology
  • Recombinant Fusion Proteins / therapeutic use
  • Signal Transduction / drug effects
  • Solubility
  • Transforming Growth Factor beta / physiology

Substances

  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • IL6 protein, human
  • IL6ST protein, human
  • Interleukin-6
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins
  • Sgp130Fc protein
  • Transforming Growth Factor beta
  • interleukin 6-interleukin 6 receptor fusion protein, recombinant
  • Cytokine Receptor gp130