Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling

Abstract

The successful treatment of certain autoimmune conditions with the humanized anti-IL-6 receptor (IL-6R) antibody tocilizumab has emphasized the clinical importance of cytokines that signal through the β-receptor subunit glycoprotein 130 (gp130). In this Review, we explore how gp130 signaling controls disease progression and examine why IL-6 has a special role among these cytokines as an inflammatory regulator. Attention will be given to the role of the soluble IL-6R, and we will provide a perspective into the clinical blockade of IL-6 activity in autoimmunity, inflammation, and cancer.

Figure 1. Receptor composition for cytokines signaling via the β-receptor subunit gp130.

gp130-related cytokines (IL-6, IL-11, IL-27, CNTF, CLC, CT-1, LIF, OSM) bind membrane-bound receptor complexes, which all contain the receptor subunit gp130. These cytokines have diverse functions, not limited to but including the induction of acute phase response protein expression; lymphocyte activation; cytoprotective actions on cardiomyocytes, neuronal cells, and hepatocytes; bone metabolism; hematopoiesis; and liver development and regeneration. IL-6 trans-signaling through the IL-6/sIL-6R complex can fulfill functions of other gp130 cytokines, including blockade of embryonic stem cell differentiation. In addition, since gp130 is expressed in all cells of the body, the IL-6/sIL-6R complex can stimulate cells in additional tissues, which do not express IL-6R, LIF receptor (LIFR), OSMR, IL-11R, CNTF receptor (CNTFR), or the IL-27 receptor subunit WSX-1.

Figure 2. Modes of therapeutic IL-6 blockade.

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.