Refining therapeutic targeting of interleukin-6 by signalling mode selectivity

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates immunity, tissue repair and metabolic homeostasis, while also driving chronic inflammation in a broad range of diseases. IL-6 exerts its effects through distinct signalling modes, including classic signalling via its membrane-bound receptor (IL-6R) and trans-signalling via the soluble IL-6R (sIL-6R), which expands IL-6 responsiveness to most if not all cell types. Therapeutic targeting of the IL-6 pathway - primarily through monoclonal antibodies neutralizing IL-6 or IL-6R and Janus kinase (JAK) inhibitors targeting downstream signalling - has transformed the treatment of several autoimmune diseases but has also highlighted safety concerns linked to the homeostatic functions of IL-6. Advances in the understanding of IL-6 signalling biology, including endogenous regulation by soluble glycoprotein 130 kDa (sgp130) and the regulation of trans-signalling by a disintegrin and metalloproteinase 17 (ADAM17), have renewed interest in strategies that allow selective pathway modulation. In this Review, we outline the molecular basis of IL-6 signalling, examine the differential roles of classic and trans-signalling in experimental and clinical disease, and compare global and selective IL-6-targeted therapeutic approaches. We focus on the emerging concept of mechanistic and clinical differentiation within the IL-6 pathway and its implications for future drug development.