2. Academic Validation
  3. Nonspecific Inhibition of IL6 Family Cytokine Signalling by Soluble gp130

Nonspecific Inhibition of IL6 Family Cytokine Signalling by Soluble gp130

  • Int J Mol Sci. 2024 Jan 23;25(3):1363. doi: 10.3390/ijms25031363.
Anissa A Widjaja 1,  Stuart A Cook 1 2 3
Affiliations

Affiliations

  • 1 Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, 8 College Road, Singapore 169857, Singapore.
  • 2 National Heart Centre Singapore, National Heart Research Institute Singapore, Singapore 169609, Singapore.
  • 3 MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London W6 8RF, UK.
PMID: 38338642 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.

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