Interleukin-6:Interleukin-6 receptor complex (IL-6:IL-6R complex)

The membrane IL-6:IL-6R complex mediating cluster signaling, also known as trans-presentation, is a signaling assembly where Interleukin-6 (IL-6) binds to the membrane-bound IL-6 receptor (mIL-6R/CD126) on one cell, and this complex then activates the signal-transducing subunit gp130 (CD130) on an adjacent cell (Heink et al., 2017, Nature Immunology). This mode of signaling is distinct from classic signaling, where IL-6 binds to mIL-6R and gp130 on the same cell, and trans-signaling, which involves soluble IL-6R (Rose-John, 2018, Cold Spring Harbor Perspectives in Biology). Cluster signaling is particularly critical for the differentiation of pathogenic Th17 cells, making it a key driver in autoimmune and inflammatory conditions such as rheumatoid arthritis and multiple sclerosis (Garbers et al., 2015, Therapeutic Advances in Musculoskeletal Disease). Because this complex is the initiator of the JAK/STAT signaling pathway, it is a primary target for monoclonal antibodies. Drugs such as tocilizumab and sarilumab bind to the IL-6R, effectively preventing the formation of the IL-6:IL-6R complex and blocking downstream signaling (Kang et al., 2019, Immunity). Understanding this specific complex is vital for developing more selective inhibitors that might spare homeostatic classic signaling while blocking the more pathogenic cluster or trans-signaling pathways.

Other names

IL-6:mIL-6R complexIL-6:CD126 complexTrans-presentation complexCluster signaling complexMembrane-bound IL-6:IL-6R complex

Monoclonal antibodies target either the IL-6 ligand or the IL-6 receptor alpha subunit (IL-6R), preventing the assembly of the IL-6:IL-6R complex on the cell membrane and its subsequent interaction with the gp130 signal transducer.