IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6

Abstract

Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with a second protein, gp130, which thereupon dimerizes and initiates intracellular signaling. Whereas gp130 is expressed on all cells, IL-6R is only present on few cells in the body including hepatocytes and some leukocytes. Cells, which do not express IL-6R cannot respond to the cytokine, since gp130 alone has no measurable affinity for IL-6. Interestingly, a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6. This process has been called trans-signaling. Here I will review published evidence that IL-6 trans-signaling is pro-inflammatory whereas classic IL-6 signaling via the membrane bound IL-6R is needed for regenerative or anti-inflammatory activities of the cytokine. Furthermore, the detailed knowledge of IL-6 biology has important consequences for therapeutic strategies aimed at the blockade of the cytokine IL-6.

Keywords: IL-6; IL-6 receptor; inflammation; inflammation associated cancer.; shedding; soluble receptor.

Fig 1

IL-6 classic- signaling and IL-6 trans-signaling. IL-6 Classic-signaling requires membrane bound IL-6R and is restricted to hepatocytes, some epithelial cells and some leukocytes. IL-6 trans-signaling requires sIL-6R and is possible on all cells of the body since all cells express the gp130 protein.

Fig 2

Receptor distribution IL-6R expressing cells. Most IL-6R expressing cells express far more gp130 than IL-6R. IL-6 stimulation of such cells leads to the activation of only few gp130 molecules. IL-6 in the presence of the sIL-6R, however, will lead to stimulation of all gp130 molecules leading to a higher signal amplitude.

Fig 3

Designer proteins for the study of IL-6 signaling. (A) Hyper-IL-6 is a fusion protein between the sIL-6R (blue) and IL-6 (brown). In a molecular model, the C-terminus of sIL-6R was 40 Å apart from the N-terminus of IL-6. Therefore, we inserted a flexible peptide linker between sIL-6R and IL-6 (black) to connect both molecules. (B) The sgp130Fc protein consists of the extracellular portion of gp130 linked to the Fc domain of a human IgG1 antibody. The sgp130Fc protein blocks IL-6 trans-signaling without affecting IL-6 classic signaling. (C) In the L-gp130 protein, the entire extracellular portion of gp130 is replaced by the leucine zipper of the Jun protein, leading to constitutive dimerization and activation of the gp130 protein. This protein can be used to study the effects of permanent gp130 activation in transfected cells or in tissue specific transgenic animals.

Fig 4

Pro- and anti-inflammatory activities of IL-6. Anti-inflammatory activities of IL-6 include STAT3 dependent regeneration of epithelial cells and the induction of the hepatic acute phase response. These activities are dependent on the membrane bound IL-6R. Pro-inflammatory activities of IL-6 include recruitment of inflammatory cells, inhibition of apoptosis of inflammatory cells and inhibition of regulatory T-cell differentiation.

Fig 5

Consequences of specific IL-6 trans-signaling blockade by sgp130Fc. The sgp130Fc protein only binds to IL-6 molecules, which are complexed with sIL-6R. Therefore, in the presence of an excess of IL-6, not all IL-6 molecules are neutralized and can induce regeneration of epithelial cells or trigger the hepatic acute phase response.