Role of IL-6 in Angiotensin II–Induced Retinal Vascular Inflammation

Retinal vascular inflammation is a common feature of blinding diseases such as diabetic retinopathy, retinopathy of prematurity (ROP), and choroidal neovascularization.1 Interleukin (IL)-6 is a potent proinflammatory cytokine involved in many pathologic processes characterized by vascular inflammation and injury, including proliferative diabetic retinopathy, choroidal neovascularization, atherosclerosis, and cancer.2–7 Vascular inflammation is a complex process that is thought to be initiated by activation of the immune system leading to increased expression of the angiogenesis/permeability factors vascular endothelial growth factor (VEGF), leukocyte attachment protein intercellular adhesion molecule (ICAM)-1, and monocyte chemotactic protein-1 (CCL-2).1,8 Previous studies have shown that IL-6 shares common characteristics with VEGF, in that both are induced by hypoxia and hyperglycemia and both play a role in vascular inflammation, vascular permeability, and pathologic angiogenesis.9–16 IL-6 has been shown to induce VEGF expression in models of choroidal neovascularization and tumor angiogenesis.4,7 However, the specific role of IL-6 in retinal vascular disease is unclear. Accumulating evidence has indicated that angiotensin II, the effector protein of the renin angiotensin system (RAS) has a fundamental role in the pathogenesis of retinal vascular diseases, including retinopathy of prematurity, proliferative diabetic retinopathy, choroidal neovascularization, and endotoxin-induced uveitis.17–22 In addition to its well-known vasoconstriction activity, angiotensin II is a potent inducer of vascular growth and inflammation. Other studies have demonstrated that intravitreal delivery of angiotensin II in rats induces VEGF expression and vascular inflammation, as shown by increased leukocyte adhesion to the retinal vessels in a process that requires reactive oxygen species (ROS) generation.18 Angiotensin II can also induce increases in VEGF expression in vitro by increasing ROS formation.23 The proinflammatory action of angiotensin II has been associated with increased expression of IL-6 in models of peripheral vascular disease. This process is thought to play a critical role in the development of vascular inflammation.6,24,25 The specific role of IL-6 in vascular injury is not yet understood, but upregulation of VEGF is thought to be involved.4,7 The purpose of this study was to investigate the mechanism by which angiotensin II induces retinal vascular inflammation and determines the specific role of IL-6 in this process.