Nonspecific Inhibition of IL6 Family Cytokine Signalling by Soluble gp130

Int J Mol Sci. 2024 Jan 23;25(3):1363. doi: 10.3390/ijms25031363.

Abstract

IL6 is a proinflammatory cytokine that binds to membrane-bound IL6 receptor (IL6R) or soluble IL6R to signal via gp130 in cis or trans, respectively. We tested the hypothesis that sgp130Fc, which is believed to be a selective IL6 trans-signalling inhibitor, is in fact a non-specific inhibitor of gp130 signalling. In human cancer and primary cells, sgp130Fc inhibited IL6, IL11, OSM and CT1 cis-signalling. The IC50 values of sgp130Fc for IL6 and OSM cis-signalling were markedly (20- to 200-fold) lower than the concentrations of sgp130Fc used in mouse studies and clinical trials. sgp130 inhibited IL6 and OSM signalling in the presence of an ADAM10/17 inhibitor and the absence of soluble IL6R or OSMR, with effects that were indistinguishable from those of a gp130 neutralising antibody. These data show that sgp130Fc does not exclusively block IL6 trans-signalling and reveal instead that broad inhibition of gp130 signalling likely underlies its therapeutic effects. This proposes global or modular inhibition of gp130 as a therapeutic approach for treating human disease.

Keywords: IL11; IL6; OSM; Olamkicept; STAT3; cis-signaling; gp130; sgp130Fc; trans-signaling.

MeSH terms

  • Animals
  • Cytokine Receptor gp130 / metabolism
  • Cytokines* / pharmacology
  • Humans
  • Interleukin-6* / metabolism
  • Mice
  • Receptors, Interleukin-6
  • Signal Transduction

Substances

  • Cytokines
  • Cytokine Receptor gp130
  • Interleukin-6
  • Receptors, Interleukin-6