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Anti-inflammatory Effect of Docosahexaenoic Acid on Cytokine-Induced Adhesion Molecule Expression in Human Retinal Vascular Endothelial Cells

¹From the Departments of Microbiology and Molecular Genetics and ²Physiology, Michigan State University, East Lansing, Michigan.

PURPOSE. Docosahexaenoic acid (DHA_22:6n3), the principal n3-polyunsaturated fatty acid (PUFA) in the retina, has been shown to have a pronounced anti-inflammatory effect in numerous in vivo and in vitro studies. Despite the importance of vascular inflammation in diabetic retinopathy, the anti-inflammatory role of DHA_22:6n3 in cytokine-stimulated human retinal vascular endothelial cells (hRVECs) has not been addressed.

METHODS. Cytokine-induced expression of cell adhesion molecules (CAMs) was assessed by Western blot. The effect of DHA_22:6n3 on cytokine-induced nuclear factor (NF)-B signaling was analyzed by Western blot analysis and electrophoretic mobility shift assay (EMSA).

RESULTS. Stimulation of hRVECs with VEGF₁₆₅, TNF, or IL-1ß for 6 to 24 hours caused significant induction of intracellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 expression. Pretreatment of the cells with 100 µM of BSA-bound DHA_22:6n3 for 24 hours remarkably inhibited cytokine-induced CAM expression. IL-1ß, TNF, and VEGF₁₆₅ induced nuclear translocation and binding of p65 and p50 NF-B isoforms to the VCAM-1 promoter. DHA_22:6n3 pretreatment inhibited cytokine-induced NF-B binding by 25% to 40%. Moreover, DHA_22:6n3 diminished IL-1ß induced phosphorylation of the inhibitor of nuclear factor (NF)-B (I-B), thus preventing its degradation.

CONCLUSIONS. IL-1ß, TNF, and VEGF₁₆₅ induced CAM expression in hRVECs through activation of the NF-B pathway. DHA_22:6n3 inhibited cytokine induced CAM expression through suppression of NF-B nuclear translocation and upstream I-B phosphorylation and degradation. DHA_22:6n3 could be an important anti-inflammatory agent in the face of increased cytokine production and CAM expression in the diabetic retina.

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