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. Author manuscript; available in PMC: 2019 Apr 1.
Published in final edited form as: Nat Rev Clin Oncol. 2018 Feb 6;15(4):234–248. doi: 10.1038/nrclinonc.2018.8

Fig. 1. IL-6 signalling pathways.

Fig. 1

a | In the classic IL-6 signalling pathway, IL-6 binds to the membrane-bound IL-6 receptor-α (subsequently referred to as IL-6R), thus inducing formation of a heterohexameric complex consisting of two molecules each of IL-6, IL-6R, and the IL-6 receptor subunit-β (gp130). Formation of this complex results in activation of the JAK/STAT3 signalling pathway, leading to the transcription of STAT3 target genes. The IL-6/IL-6R/gp130 complex can also activate the PI3K/AKT/mTOR (mechanistic target of rapamycin) and RAS/RAF/MEK/ERK pathways (not pictured). b | In the IL-6 trans-signalling pathway, soluble IL-6R (sIL-6R) binds to IL-6. sIL-6R can be generated by alternative splicing of IL6R mRNA or cleavage of membrane-bound IL-6R by disintegrin and metalloproteinase domain-containing protein 170(ADAM10) or ADAM17. When IL-6 binds with sIL-6R, this complex is then able to bind to and induce the dimerization of gp130, leading to the activation of downstream signalling pathways (as described above for classic IL-6 signalling pathways). gp130 is ubiquitously expressed, although the IL-6R is expressed in only a limited number of cell types. Trans-signalling via sIL-6R enables IL-6 to act on cells with limited or absent IL-6R expression. IL-6 trans-signalling can be negatively regulated by soluble gp130 (sgp130), which is generated by alternative splicing. This molecule competes with membrane-bound gp130 for binding to the IL-6–sIL-6R complex, thereby inhibiting IL-6 trans-signalling but not the classic IL-6 signalling pathway.