Interleukin-6 (IL-6) mediates protection against glucose toxicity in human Müller cells via activation of VEGF-A signaling

Interleukin-6 (IL-6) has become a target of interest for drug development aiming to treat diabetic retinopathy. Since IL-6 signaling can promote beneficial as well as detrimental effects via two different signaling pathways, the objective of the present study was to investigate the effects of classical IL-6 and IL-6 trans-signaling on human Müller cells (HMC), which are important for the development of diabetic retinopathy. HMCs were cultured in normal (5 mmol/L) and high (25 mmol/L) glucose plus or minus IL-6 or IL-6/sIL-6R. IL-6 receptor expression using immunohistochemistry and flow cytometry and cytokine release using magnetic bead assays were determined. HMCs express the membrane bound form of the IL-6 receptor (mIL-6R), gp130, and can release the soluble forms sIL-6R and sgp130 demonstrating that HMCs are capable of responding to classical IL-6 and IL-6 trans-signaling. IL-6 protected HMCs from glucose toxicity via VEGF-A signaling. IL-6/sIL-6R caused only modest protection, which was not mediated by VEGF-A. Our data show for the first time that classical IL-6 signaling exerts its beneficial effects through VEGF-A action contrary to IL-6 trans-signaling, which was VEGF-A independent. These results have clinical implications for drug development targeting IL-6 since strict anti-IL-6 therapies might further decrease neuroretinal functions in the diabetic retina. [Display omitted] •Human Müller cells express mIL-6R and gp130 allowing for classical IL-6 signaling.•Hyperglycemia upregulates mIL-6R and gp130 expression.•IL-6 via classical signaling induces VEGF-A signaling in human Müller cells.•IL-6-induced VEGF-A production protects human Müller cells from glucose toxicity.•Human Müller cells only weakly respond to IL-6 trans-signaling.