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J.V. Busik, W. Chen, D. Jump, M. Grant, W. Esselman; Anti–Inflammatory Effect of Docosahexaenoic Acid (DHA, 22:6,n3), on VEGF, TNF and IL–1ß–Induced Adhesion Molecule Expression in Human Retinal Vascular Endothelial Cells . Invest. Ophthalmol. Vis. Sci. 2004;45(13):1097.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Early stage diabetic retinopathy has been hypothesized to result from a low–grade chronic inflammatory condition. The mechanisms leading to pro–inflammatory changes in the retina are not well understood, but are likely to involve carbohydrate and lipid metabolic disorders. Insulin controls an array of enzymes and signaling molecules involved in lipogenesis and lipid metabolism, resulting, for instance, in the decrease in n3/n6 ratio and a decrease in long chain n3 polyunsaturated fatty acids such as DHA. We have previously demonstrated that n6 fatty acids cause pro–inflammatory changes in human retinal vascular endothelial cells (hRVE). The purpose of this study was to examine the effects of n3 polyunsaturated fatty acids on cytokine–induced inflammatory changes in hRVE. Methods:hRVE cells were treated with cytokines in the presence or absence of DHA. Fatty acids composition of hRVE cells before and after treatment was measured by RP–HPLC and GC–MS. The expression of adhesion molecules such as intercellular adhesion molecules–1 (ICAM–1) and vascular adhesion molecules (VCAM)–1 was assayed by Western Blotting. Cytokine–induced NFΚB binding to VCAM–1 promoter was assayed by EMSA. Results: Treatment of hRVE cells with 20 ng/ml VEGF, 5 ng/ml TNFα or 1 ng/ml IL–1ß for 6–24 hours caused 10–15 fold induction of ICAM–1 and VCAM–1 expression. Pre–treatment of the cells for 24 hours with 100 µM of BSA–bound DHA completely inhibited cytokine–induced CAM expression. Pre–treatment with saturated palmitic acid (16:0) did not affect cytokine–induced CAM expression. VEGF and TNFα induced NFΚB binding to VCAM–1 promoter. Pre–treatment with DHA, but not with palmitic acid, blocked VEGF–induced NFΚB binding to VCAM–1 promoter. Conclusions:DHA is a potent inhibitor of VEGF, TNFα and IL–1ß induced CAM expression in hRVE cells. Dysregulation of fatty acid metabolism resulting in changes of fatty acid profile with decrease in DHA could lead to the increase in cytokine–induced pro–inflammatory signaling in retinal microvasculature in diabetes.
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