IL-1\(\beta\) Is Upregulated in the Diabetic Retina and Retinal Vessels: Cell-Specific Effect of High Glucose and IL-1\(\beta\) Autostimulation

Many molecular and cellular abnormalities detected in the diabetic retina support a role for IL-1b-driven neuroinflammation in the pathogenesis of diabetic retinopathy. IL-1b is well known for its role in the induction and, through autostimulation, amplification of neuroinflammation. Upregulation of IL-1b has been consistently detected in the diabetic retina; however, the mechanisms and cellular source of IL-1b overexpression are poorly understood. The aim of this study was to investigate the effect of high glucose and IL-1b itself on IL-1b expression in microglial, macroglial (astrocytes and Müller cells) and retinal vascular endothelial cells; and to study the effect of diabetes on the expression of IL-1b in isolated retinal vessels and on the temporal pattern of IL-1b upregulation and glial reactivity in the retina of streptozotocin-diabetic rats. IL-1b was quantified by RealTime RT-PCR and ELISA, glial fibrillar acidic protein, a2-macroglobulin, and ceruloplasmin by immunoblotting. We found that high glucose induced a 3-fold increase of IL-1b expression in retinal endothelial cells but not in macroglia and microglia. IL-1b induced its own synthesis in endothelial and macroglial cells but not in microglia. In retinal endothelial cells, the high glucose-induced IL-1b overexpression was prevented by calphostin C, a protein kinase C inhibitor. The retinal vessels of diabetic rats showed increased IL-1b expression as compared to non-diabetic rats. Retinal expression of IL-1b increased early after the induction of diabetes, continued to increase with progression of the disease, and was temporally associated with upregulation of markers of glial activation. These findings point to hyperglycemia as the trigger and to the endothelium as the origin of the initial retinal upregulation of IL-1b in diabetes; and to IL-1b itself, via autostimulation in endothelial and macroglial cells, as the mechanism of sustained IL-1b overexpression. Interrupting the vicious circle triggered by IL-1b autostimulation could limit the progression of diabetic retinopathy. Citation: Liu Y, Biarnés Costa M, Gerhardinger C (2012) IL-1b Is Upregulated in the Diabetic Retina and Retinal Vessels: Cell-Specific Effect of High Glucose and IL1b Autostimulation. PLoS ONE 7(5): e36949. doi:10.1371/journal.pone.0036949 Editor: Kathrin Maedler, University of Bremen, Germany Received November 3, 2011; Accepted April 16, 2012; Published May 16, 2012 Copyright: 2012 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Institutes of Health (R01EY016206). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected]