Interleukin-6 “Trans-Signaling” and Ischemic Vascular Disease: The Important Role of Soluble gp130

Figure 1

IL-6 signal transduction via classic and trans-signaling. The upper part of the figure depicts IL-6 signaling in cells expressing the membrane-bound receptor for IL-6 (IL-6R). In these cells (e.g., hepatocytes and several white blood cells), circulating IL-6 binds directly to IL-6R that forms a signaling complex with the membrane-bound glycoprotein 130 (gp130); this pathway is known as classic signaling. The bottom part depicts the IL-6 signaling in those cells that do not express the membrane-bound IL-6R. In these cells, membrane-bound gp130 (ubiquitously expressed) is activated by the circulating IL-6/sIL-6R complex (composed of IL-6 and the circulating soluble portion of IL-6R, sIL-6R). This pathway, known as trans-signaling, could be inhibited by the circulating soluble portion of gp130 (sgp130), which, by means of binding the circulating IL-6/sIL-6R complex, blocks the activation of the membrane-bound gp130. sgp130fc is a recombinant fusion protein of soluble gp130 and human IgG1 Fc that blocks IL-6 trans-signaling mimicking sgp130 functions.