IL-6, IL-17 and STAT3: a holy trinity in auto-immunity?

ABSTRACT

Interleukin-6 (IL-6) is a pleiotropic cytokine involved in the regulation of the cross talk between haematopoietic/immune cells and stromal cells, including the onset and resolution of inflammation, responses to infection, tissue remodelling and cancer. It is produced, among others, by fibroblasts, endothelial cells, macrophages and lymphocytes. IL-6 can interact with both membrane-bound and soluble forms of its ligand-binding receptor, the IL-6Ralpha, triggering signalling via dimerization of gp130, the signalling subunit of the IL-6 receptor complex. This leads to the activation of the JAK/STAT pathway and mainly culminates in the activation of the STAT3 transcription factor. Both IL-6 and STAT3 have recently emerged as main regulators of the differentiation and function of Th17 cells, via a positive feedback loop enhancing expression and/or activation of IL-6 itself, IL-17 and STAT3. Dysregulated IL-6 production and signalling are associated with chronic inflammatory diseases, auto-immunity and cancer, and are the object of intense translational research as promising therapeutic targets.