Biomarkers of Disease: IL-6-type cytokines and signalling in inflammation

Interleukin (IL)-6 was identified as a hepatocyte-stimulating factor more than 10 years ago [1]. Subsequently, the authors have proposed IL-6 to be the major mediator of acute phase protein synthesis in liver cells. IL-6 belongs to the so-called IL-6-type cytokine family comprising, additionally, IL-11, leukaemia inhibitory factor (LIF), oncostatin M (OSM), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT-1). The members of this cytokine family exert pro- as well as anti-inflammatory activities via surface receptors. For IL-6 and IL-11, these surface receptors comprise specific α -receptors and two identical gp130 signal transducer molecules, while, for other IL-6-type cytokines such as CNTF, OSM, LIF and CT-1, one gp130 and one LIF-receptor are involved. Resolution of the three-dimensional structures of IL-6, LIF and CNTF shows that the three cytokines form a bundle of four antiparallel long-chain alpha-helices of an up-up-down-down topology that are connected by loops. The amino acid residues involved in the interaction between IL-6, its α -receptor and the signal transducer gp130 have been identified by several groups including that of the authors. Recently, tyrosine 190, phenylalanine 191 and valine 252 of gp130 were identified as important residues for the binding and signalling of IL-6 and IL-11 [2]. IL-6 signalling: within the cytoplasm Early in 1994, the major steps in IL-6 signalling were elucidated [3, 4], clarifying how signals reach the cell nucleus and regulate acute phase protein genes such as C-reactive protein, fibrinogen, haptoglobin or hemopexin. A schematic representation is shown in Figure 24.1. IL-6 first binds to its α -receptor (gp80).