IL-6 receptor (IL-6R), is a protein complex consisting of IL-6Rα ( also known as CD126) and interleukin 6 (IL-6) signal transducer (IL6ST/GP130/IL6-beta), a receptor subunit also shared by many other cytokines. Dysregulated production of IL-6R and its ligands are implicated in the pathogenesis of many diseases, such as multiple myeloma, autoimmune diseases and prostate cancer. Alternatively spliced transcript variants encoding distinct isoforms have been reported.
The fully competent IL-6 receptor (IL-6R) is composed of an 80-kilodalton type 1 cytokine a-receptor subunit (IL-6R; also known as CD126), which binds IL-6, and a universally expressed 130-kilodalton signal-transducing b-receptor subunit (gp130; also known as CD130; encoded by IL6ST). Structure-function studies predict that a functioning IL-6 receptor requires the formation of an IL-6–IL-6R–gp130 complex that is clustered into a dimer structure.
The human IL-6R protein contains 468 amino acids, which includes a signal peptide, an extracellular region, a transmembrane domain, and a short cytoplasmic domain of 19, 339, 28, and 82 amino acids, respectively.
Scientists have reported the x-ray structure (2.4 Å) of the IL-6R ectodomains. The N-terminal strand of the Ig-like domain (D1) is disulfide-bonded to domain D2, and domains D2 and D3, the cytokine-binding domain, are structurally similar to known cytokine-binding domains. The head-to-tail packing of two closely associated IL-6R molecules observed in the crystal may be representative of the configuration of the physiological dimer of IL-6R and provides new insight into the architecture of the IL-6R complex.
IL-6 receptor (IL-6R) is important for ligand binding. IL-6 exerts its biological activities through two molecules: IL-6R and gp130. IL-6R is a non-signaling receptor that binds with IL-6. The gp130 subunit is the signal transducing receptor for interleukin 6 (IL-6) and its related family members.
When IL-6 binds to mIL-6R (membrane-bound form of IL-6R), homodimerization of gp130 (also referred to as IL-6Rβ or CD130) is induced and a high-afﬁnity functional receptor complex of IL-6, IL-6R and gp130 is formed. Interestingly, sIL-6R (soluble form of IL-6R) also binds with IL-6, and the IL-6–sIL-6R complex can then form a complex with gp130. However, this trans-signalling is thought to be highly regulated by sgp130 (soluble gp130), which exists in higher concentrations in circulating blood. sgp130 binds to the IL-6–sIL-6R complex and thereby inhibits the binding of the IL-6–sIL-6R complex to mgp130(membrane-bound gp130). Thus sgp130 is a natural inhibitor of IL-6 signalling. This unique receptor signalling system is termed IL-6 trans-signalling.
Once the IL-6 receptor complex is engaged there are multiple downstream events that allow IL-6 to mediate its diverse effects. The homodimerization of receptor complex activates JAKs (Janus kinases) that then phosphorylate tyrosine residues in the cytoplasmic domain of gp130. The gp130-mediated JAK activation by IL-6 triggers two main signalling pathways: the gp130 Tyr759-derived SHP-2/ERK MAPK pathway and the gp130 YXXQ-mediated JAK/STAT pathway.
Tocilizumab is a humanized anti-IL-6R monoclonal Ab of the IgG1 class that was generated by grafting the complementarity determining regions of a mouse antihuman IL-6R Ab onto human IgG1, and it blocks IL-6-mediated signal transduction by inhibiting IL-6 binding to transmembrane and soluble IL-6R.
Tocilizumab has resulted in the approval of this biologic for the treatment of rheumatoid arthritis (RA) in more than 100 countries, as well as for systemic and polyarticular juvenile idiopathic arthritis and Castleman's disease.
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