Interleukin-6 trans-signaling complex (IL-6/sIL-6R complex)

The Interleukin-6 (IL-6) trans-signaling complex is a heterotrimeric assembly formed when the cytokine IL-6 binds to the soluble form of its receptor (sIL-6R). While classic IL-6 signaling is restricted to cells expressing membrane-bound IL-6R (primarily hepatocytes and certain leukocytes), the IL-6/sIL-6R complex can activate virtually any cell type because its signal-transducing subunit, glycoprotein 130 (gp130), is ubiquitously expressed (Rose-John, S., 2012, 'IL-6 trans-signaling via the soluble IL-6 receptor'). This trans-signaling mechanism is predominantly responsible for the pro-inflammatory effects of IL-6, contributing to the pathogenesis of chronic inflammatory diseases like Crohn's disease and rheumatoid arthritis, as well as promoting tumor progression and cardiovascular inflammation (Garbers, C., et al., 2018, 'Interleukin-6 signaling and therapeutics'). Therapeutic strategies specifically target this complex using soluble gp130-Fc fusion proteins, such as Olamkicept, which act as a molecular trap to neutralize the IL-6/sIL-6R complex. By selectively blocking trans-signaling while sparing the regenerative and anti-inflammatory classic signaling pathway, these agents aim to provide a more targeted anti-inflammatory effect with a potentially superior safety profile compared to global IL-6 or IL-6R inhibitors (Schreiber, S., et al., 2021, 'Therapeutic targeting of IL-6 trans-signaling').

Other names

IL-6/soluble interleukin-6 receptor complexIL-6/sIL-6R/gp130 complexHyper-IL-6Soluble IL-6 receptor complex

Selective inhibition of IL-6 trans-signaling by sequestering the IL-6/sIL-6R complex, thereby preventing its binding to membrane-bound gp130 without affecting classic IL-6 signaling.