The role of interleukin-6 signalling and its therapeutic blockage in skewing the T cell balance in rheumatoid arthritis

Therapeutic blockage of cytokine signalling in autoimmune diseases has improved our understanding of the role of these cytokines in triggering, shaping and perpetuating autoimmune responses. In rheumatoid arthritis (RA), immunopathology is driven by a predominance of arthritogenic T helper cells secreting interferon- [T helper type 1 (Th1)] and interleukin (IL)-17 (Th17) over regulatory T cells (T-reg). The pleiotropic cytokine IL-6 is crucial to the differentiation of Th17 cells and the balance between pathogenic Th17 and protective T-reg. Targeting the IL-6 receptor (IL-6R) by humanized antibodies improves signs and symptoms of RA, and has provided new insights into the mechanisms of inflammation and immune regulation. Here we review current evidence on the role of IL-6 in the pathogenesis of RA and the molecular consequences of IL-6R blockage in disease, with special focus on the Th17/T-reg balance and plasticity.