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Modesto A. Rojas, Wenbo Zhang, Zhimin Xu, Doan T. Nguyen, Robert W. Caldwell, Ruth B. Caldwell; Interleukin 6 has a Critical Role in Diabetes-induced Retinal Vascular Inflammation and Permeability. Invest. Ophthalmol. Vis. Sci. 2011;52(14):1003.
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Vascular inflammation plays a critical role in the development of diabetic retinopathy (DR). Interleukin (IL)-6 is a potent proinflammatory cytokine. Increased IL-6 expression in the vitreous of DR patients is correlated with macular edema. Yet, the specific role of IL-6 in the pathogenesis of DR remains to be elucidated. Here we determined whether IL-6 is involved in vascular inflammation and leakage in a mouse model of diabetic retinopathy.
Wild type C57BL6 (WT) and IL-6 deficient (IL-6ko) mice were injected intraperitoneally with streptozotozin (75 mg/kg) to induce diabetes. WT mice were used as controls. After 4 weeks of hyperglycemia, vascular inflammation was determined by using an assay for leukostasis. Mice were anesthetized, perfused with Concanavalin A and the number of adherent leukocytes was counted in retinal flat mounts. For immunohistochemistry analysis, total blood was washed out by perfusion with. Eye balls were fixed in 4% paraformaldhehyde and frozen sections were prepared. Localization of VEGF and TNF-alpha was determined by labeling retinal sections with specific antibodies together with a maker for microglia (Iba1). Retinal vascular leakage was determined by immunolabeling with anti-albumin antibody and quantified with Metamorph Software.
To address the role of IL-6 in diabetes-induced retinal vascular inflammation and leakage, leukostasis and albumin extravasation were determined in WT and IL-6ko mice. Diabetes induced a 2.2 fold increase in the number of leukocytes adherent to the retinal vessels and a 5.2 fold increase in the relative albumin extravasation into the retinal parenchyma. These increases were dramatically reduced by more than 75% in the IL-6ko mice. Analysis of VEGF expression in retina sections did not reveal a significant change in the diabetic retina as compared with control, suggesting a minimal role of VEGF in the above changes. TNF-alpha is a known player in diabetic retinopathy as initiator of inflammation and inducer of vascular permeability. Analysis of TNF-alpha levels revealed that it is prominently increased in microglial cells localized in the nerve fiber and inner and outer plexiform layers. However, this increase was blocked and reduced to the control level by IL-6ko.
These studies indicate that IL-6 has an important role in the pathogenesis of diabetic retinopathy by serving as a mediator of vascular inflammation and vascular leakage. The action of IL-6 may involve its regulation of TNF-alpha production in the disease.
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