Fig 2.

IL-6 ‘classical’ signalling, IL-6 ‘trans-signalling’ and inhibition of ‘trans-signalling’. (A) In the classical signalling IL-6 binds to the membrane-bound IL-6 receptor. (B) In trans-signalling IL-6 binds to the soluble IL-6 receptor, previously released from some cells. This complex is interacting with membrane-associated gp130. In both, classical and trans-signalling, the signal-transducer gp130 is recruited and STAT3 phosphorylation is activated. This can be achieved by PKC-γ. Other signal pathways may also be activated (box with green double frame), resulting in STAT3 phosphorylation. Subsequently, STAT3 activates gene expression in the nucleus. Among the genes activated by IL-6 is SOCS3, a down-regulator of IL-6 signalling. Some additional genes and functions relevant for atherosclerosis are mentioned in the yellow box. (C) Inhibition of trans-signalling by soluble gp130. Soluble gp130 is generated by alternative splicing. This molecule can bind the complex of soluble IL-6 receptor and IL-6, but not IL-6 alone. Thus, soluble gp130 is a selective inhibitor of IL-6 trans-signalling. (D) The definitions of the different symbols are provided in the yellow box. The definitions of the different symbols include another type of soluble gp130 [soluble gp130 (eng.)], which refers to a dimeric sgp130 engineered by molecular biological methods, which is a more effective inhibitor of trans-signalling than natural soluble gp130.