IL-6 signaling and inhibition by tocilizumab. (A) Classic IL-6 signaling restricted to IL-6R–expressing cells shown in pink (macrophages, neutrophils, T cells, and hepatocytes), which predominates when IL-6 levels are low. IL-6 binds to cell-associated IL-6R, leading to homodimerization of gp130 and initiation of downstream pathways. (B) Both classic and trans-IL-6 signaling, which occurs when IL-6 levels are elevated, leading to IL-6 signaling on a broad array of cells, because gp130 is ubiquitously expressed. Tocilizumab binding to both cell-associated IL-6R and soluble IL-6R inhibits classic and trans-signaling. IL-6R–expressing cells are shown in pink, whereas non-IL-6R–expressing cells are shown in blue.