Specific targeting of IL-6 signalling pathway: a new way to treat IBD?

More than 200 cytokines have been identified that bind to specific receptors expressed on the surface of the target cells. They are able to trigger intracellular signalling cascades leading to the control of gene expression involved in the cellular response. Although a lot of detailed information on the signalling cascade and effects of specific cytokines on various cells has accumulated over the past few years, our understanding of cytokine functions in vivo remains very poor. These uncertainties are particularly illustrated by the case of interleukin (IL)-6. The in vivo functions of this cytokine remain debated, IL-6 being considered alternatively as a pro- or anti-inflammatory cytokine,1 2 or sometimes as a key factor to polarise Th2 cells.3 Moreover, the IL-6 signalling is particular involving a phenomenon called trans signalling.4 Briefly, the receptor for IL-6 consists of two subunits: a ligand binding component (IL-6R) and a signal-transducing glycoprotein 130 (gp130) which is a member of the cytokine receptor superfamily (including also IL-11 and the leukaemia inhibitory factor). A soluble form of the ligand specific chain (sIL-6R), when complexed to IL-6, is capable of binding to the membrane bound gp130 and thus can elicit a signal-transduction involving STAT-3.5 This phenomenon called trans signalling introduced a novel aspect of cytokine action (fig 1). Figure 1 The receptor for IL-6 consists of the ligand binding component (IL-6R) and the signal-transducing gp130. The soluble form of the IL-6R may form a complex with IL-6 having the ability to bind gp130 (trans signaling) expressed by T cells and to activate the anti-apoptotic STAT-3 dependent genes bcl-2 and bcl-xl. In inflammatory diseases, targeting of IL-6 signaling pathway modulates inflammation at least in part through the regulation of T cell expansion and the expression of adhesion molecules. In …