The tumor necrosis factor superfamily members TWEAK, TNFSF15 and fibroblast growth factor-inducible protein 14 are upregulated in proliferative diabetic retinopathy.

Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and tumor necrosis factor superfamily member 15 (TNFSF15), members of the TNF superfamily, play important roles in the modulation of inflammation and neovascularization. TWEAK activity is mediated via binding to fibroblast growth factor-inducible molecule 14 (Fn14). We investigated the expression of TWEAK, Fn14 and TNFSF15 and the correlation between TWEAK levels and the levels of the inflammatory biomarker soluble intercellular adhesion molecule-1 (sICAM-1) in proliferative diabetic retinopathy (PDR). In addition, we examined the expression of FN14 and TNFSF15 in retinas of diabetic rats. Vitreous samples from 34 PDR and 23 nondiabetic patients were studied by enzyme-linked immunosorbent assay and Western blot analysis. Epiretinal membranes from 14 patients with PDR were studied by immunohistochemistry. The retinas of rats were examined by Western blot analysis. We identified a significant increase in the expression of TWEAK, Fn14, TNFSF15 and sICAM-1 in vitreous samples from PDR patients compared to controls. A significant positive correlation was found between levels of TWEAK and levels of sICAM-1 (r = 0.3, p = 0.02). In epiretinal membranes, TWEAK and TNFSF15 protein expression was confined to vascular endothelial cells, monocytes/macrophages and myofibroblasts. Significant positive correlations were observed between the number of blood vessels expressing CD34 and the number of blood vessels expressing TWEAK (r = 0.670; p = 0.017) and TNFSF15 (r = 0.784; p = 0.001). The expression level of TNFSF15 was upregulated in the retinas of diabetic rats, whereas Fn14 was not upregulated. Our findings suggest that TNFSF15 and the TWEAK/Fn14 pathway are novel mediators involved in persistent inflammation and modulation of pathological neovascularization associated with PDR.