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

The Interleukin-6 (IL-6) receptor signaling complex is a multi-protein assembly essential for mediating the pleiotropic effects of the cytokine IL-6 [UniProt: P05231, P08887]. It typically forms a hexameric structure comprising two molecules each of IL-6, the IL-6 receptor alpha subunit (IL-6R or CD126), and the signal-transducing subunit glycoprotein 130 (gp130 or CD130) [PMID: 17465721]. Signaling occurs through three distinct modes: classic signaling via membrane-bound IL-6R, trans-signaling via soluble IL-6R, and cluster signaling [PMID: 30212350, UniProt: P40189]. These pathways lead to the dimerization of gp130 and subsequent activation of the Janus kinase/Signal transducer and activator of transcription (JAK/STAT) pathway [PMID: 31515941]. This complex plays a pivotal role in regulating immune responses, inflammation, hematopoiesis, and the acute phase response [StatPearls: Interleukin 6]. Dysregulation of IL-6 signaling is linked to chronic inflammatory diseases, autoimmune disorders like rheumatoid arthritis, and life-threatening conditions such as cytokine release syndrome and COVID-19 [PMID: 32511329]. Consequently, components of this complex are major therapeutic targets for monoclonal antibodies. Drugs like tocilizumab and sarilumab block the IL-6 receptor, while siltuximab targets the IL-6 ligand, both preventing the assembly of the functional signaling complex [FDA Label: Actemra, Kevzara].

Other names

IL-6/IL-6R/gp130 complexInterleukin-6 receptor complexIL-6 signaling complexIL-6/sIL-6R/gp130 complexIL-6 trans-signaling complex

Drugs targeting this complex typically act as monoclonal antibodies that bind either to the IL-6 ligand or the IL-6 receptor alpha subunit (IL-6R), thereby preventing the assembly of the hexameric signaling complex with gp130 and inhibiting the downstream JAK/STAT, MAPK, and PI3K/Akt signaling pathways [PMID: 17465721, 31515941].