Interleukin-6 receptor–gp130 complex (IL-6R/gp130)

The Interleukin-6 receptor–gp130 complex is a multi-subunit signaling assembly essential for mediating the pleiotropic effects of Interleukin-6 (IL-6) (NIH, 2021). It typically consists of the IL-6 ligand, the IL-6 receptor alpha subunit (IL-6R or CD126), and the signal-transducing beta subunit glycoprotein 130 (gp130 or CD130) (NIH, 1.1.2). Signaling can occur via classic signaling on cells expressing both subunits or trans-signaling, where soluble IL-6R binds IL-6 and activates gp130 on cells that do not express IL-6R (J Clin Invest, 2011). This complex activates the JAK/STAT (primarily STAT3), MAPK, and PI3K pathways, driving processes such as the immune response, hematopoiesis, and the acute-phase reaction (NIH, 2021; ResearchGate, 2024). Dysregulation of this complex is a hallmark of chronic inflammatory diseases, autoimmune disorders like rheumatoid arthritis, and various cancers (NIH, 2021; J Med Chem, 2014). Therapeutic strategies include monoclonal antibodies that block IL-6 or IL-6R, and fusion proteins like sgp130Fc that selectively inhibit trans-signaling (J Clin Invest, 2011).

Other names

IL-6/IL-6R/gp130 complexInterleukin-6 receptor complexgp130/IL-6R complexCD126/CD130 complexInterleukin-6 receptor subunit alpha/Glycoprotein 130 complex

Drugs targeting this complex primarily act by preventing its assembly or signaling. Monoclonal antibodies like tocilizumab and sarilumab bind to the IL-6 receptor alpha subunit (IL-6R), while siltuximab binds directly to the IL-6 ligand, both preventing the formation of the hexameric signaling complex with gp130 (Mihara et al., 2005; NIH, 2021). Soluble gp130-Fc fusion proteins, such as olamkicept, specifically target the IL-6/sIL-6R complex to inhibit trans-signaling without affecting classic signaling (J Clin Invest, 2011). Additionally, small molecules like raloxifene can bind to the gp130 D1 domain to disrupt the interaction between the IL-6/IL-6R complex and gp130, thereby inhibiting downstream JAK/STAT3 signaling (J Med Chem, 2014).