IL-6–neutralizing antibodies (violet; Table 1) block both classical and trans-signaling of IL-6 by interfering with binding of IL-6 to IL-6R. This might lead to high-level accumulation of IL-6 due to decreased clearance. IL-6R–neutralizing antibodies interfere with binding of IL-6R to IL-6 (green; Table 1) and also block both classical and trans-signaling of IL-6 but only lead to moderate elevation of IL-6 levels due to impaired internalization and subsequent degradation of IL-6. The sgp130Fc protein (red/brown; Table 1) specifically blocks IL-6 trans-signaling without affecting classical signaling via the membrane-bound IL-6R, since IL-6 alone has no measurable affinity to sgp130Fc.