The Soluble Interleukin 6 Receptor: Advanced Therapeutic Options in Inflammation

Clin Pharmacol Ther. 2017 Oct;102(4):591-598. doi: 10.1002/cpt.782. Epub 2017 Jul 29.

Abstract

Interleukin (IL)-6 binds to IL-6R and the complex of IL-6 and IL-6R associates with the receptor subunit gp130, which initiates signaling. gp130 is expressed on all cells. IL-6R is cleaved by the ADAM17, generating a soluble IL-6R (sIL-6R). The sIL-6R binds IL-6 and the complex of IL-6 and sIL-6R binds to gp130 even on cells that do not express IL-6R. This process, which has been called IL-6 trans-signaling, increases the spectrum of target cells for IL-6. We generated a protein, sgp130Fc, which inhibits IL-6 trans-signaling without affecting IL-6 classic signaling. Using the sgp130Fc protein we demonstrated that IL-6 classic signaling is antiinflammatory and protective, whereas IL-6 trans-signaling is proinflammatory. Blocking IL-6 trans-signaling does not compromise the defense of the body against bacterial infections. We suggest that sgp130Fc is a superior agent as compared to IL-6 or IL-6R antibodies to block IL-6. The sgp130Fc protein is in phase II clinical trials.

Publication types

  • Review

MeSH terms

  • Animals
  • Cytokine Receptor gp130 / metabolism
  • Drug Design
  • Humans
  • Inflammation / drug therapy*
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism*
  • Receptors, Interleukin-6 / immunology
  • Receptors, Interleukin-6 / metabolism*
  • Recombinant Fusion Proteins / administration & dosage*
  • Signal Transduction / drug effects

Substances

  • Interleukin-6
  • Receptors, Interleukin-6
  • Recombinant Fusion Proteins
  • Sgp130Fc protein
  • Cytokine Receptor gp130