IL-6 in diabetes and cardiovascular complications

Abstract

IL-6 is a pleiotropic cytokine that participates in normal functions of the immune system, haematopoiesis, metabolism, as well as in the pathogenesis of metabolic and cardiovascular diseases. Both pro- and anti-inflammatory roles of IL-6 have been described, which are distinguished by different cascades of signalling transduction, namely classic and trans-signalling. The present review summarizes the basic principles of IL-6 signalling and discusses its roles in diabetes and associated cardiovascular complications, with emphasis on the different outcomes mediated by the two modes of IL-6 signalling and the value of developing therapeutic strategies to specifically target the deleterious trans-signalling of IL-6.

Keywords: cardiovascular diseases; diabetes; inflammation; interleukin-6.

© 2014 The British Pharmacological Society.

Figures

Figure 1

The intracellular IL-6 signal transduction is initiated by dimerization of gp130 through binding of IL-6/IL-6R (classic signalling, left panel) or IL-6/sIL-6R (trans-signalling, right panel) to gp130. Phosphorylation of tyrosine residues in gp130 upon dimerization leads to activation of three gp130 signalling pathways: JAK/STAT pathway (middle), SHP2/MAPK pathway (left) and PI3K/Akt pathway (right). SHP2, SRC homology domain 2-containing tyrosine phosphatase 2; PI3K, phosphatidylinositol 3-kinase.

Figure 2

The pleiotropic role of IL-6 is demonstrated by its differential actions on various tissues and organs, which partly depends upon whether the classic signalling or trans-signalling is involved. The diagram illustrates features relevant to metabolic regulation and disorders, and cardiovascular complications. There are three sources of elevated plasma IL-6 – adipose tissue in diabetes and obesity, contracting skeletal muscle during exercise and vascular smooth muscle cells in atherosclerotic plaques (upper panel). Given the presence of membrane-bound IL-6R in hepatocytes and pancreatic islet cells, IL-6 is most likely to elicit its effects in liver and pancreas through classic signalling (left); whereas in skeletal muscle and the vascular wall, IL-6 acts through trans-signalling, because these cells lack expression of membrane-bound IL-6R (right).