Preretinal proliferative membrane formation, which is regulated by various cytokines, is a very important step in the pathogenesis of proliferative diabetic retinopathy. In addition to vascular endothelial growth factor, transforming growth factor β2 (TGF-β2) has been shown to play a key role in preretinal membrane formation caused by retinal metabolic abnormalities. Interleukin 6 (IL-6) has also been reported to be involved in the pathogenesis of diabetic retinopathy. In this study, to investigate the roles of these cytokines in the pathogenesis of diabetic retinopathy, we searched for systemic and/or ocular factors relevant to TGF-β2 and IL-6 in diabetic eyes.

The concentrations of TGF-β2 and IL-6 in the vitreous fluid derived from 92 eyes of 92 diabetic patients (mean ±SD age, 50.5 ± 12.3 years) and 4 eyes of 4 nondiabetic patients (mean ±SD age, 60 ± 14.7 years) were measured using enzyme-linked immunosorbent assay kits (R&D System, Minn). The mean age was not different between the 2 groups. Four eyes from the patients with background diabetic retinopathy and 86 eyes from the patients with active proliferative diabetic retinopathy were included. Vitreous fluid was obtained during vitrectomy under the approval from the authority of the institutional review board with informed consent from each patient. The correlation between the concentrations and the clinical factors was examined statistically.

The concentrations of IL-6 in proliferative diabetic retinopathy eyes ranged from 3.1 to 191.0 pg/mL, with a mean ±SD of 37.6 ± 43.6 pg/mL (n=20), which was significantly higher than those in nondiabetic eyes (3.2 ± 2.3 pg/mL, n=3) (Mann-Whitney U test, P=0.01). Multivariate regression analysis using a logistic model was performed to search for the relevant factor(s) to the concentration of IL-6 among duration of diabetes, blood glucose control evaluated by hemoglobin A_1C values, grade of diabetic retinopathy, treatment by laser photocoagulation, grade of vitreous hemorrhage, macular edema, tractional retinal detachment, posterior vitreous detachment, and the concentration of vascular endothelial growth factor. The analysis revealed that the concentration of IL-6 was significantly correlated with hemoglobin A_1C (n=18, P=0.003). This correlation is consistent with the result from the report that high glucose levels stimulated IL-6 production from monocytes. These results show that IL-6 in eyes with diabetic retinopathy was associated with poor diabetic control, which may cause diabetic retinopathy progression.

The concentration of total TGF-β2 ranged from 1400 to 5200 pg/mL with a mean ±SD of 2616 ±1135 pg/mL (n=15). Multivariate regression analysis was also performed to search for the relevant factor(s) to the concentration fo TGF-β2 among hemoglobin A_1C, grade of retinopathy, grade of vitreous hemorrhage, macular edema, and tractional retinal detachment. Transforming growth factor β2 was significantly correlated with the grade of vitreous hemorrhage (n=14, P=0.004) (vitreous hemorrhage was graded by the visibility of ocular fundus). Transforming growth factor β2 has been reported to be involved in the formation of proliferative membranes and in the contraction of those membranes. These results indicate that TGF-β2 was involved in the pathogenesis of vitreous hemorrhage.

This study reveals the correlation between IL-6 and hyperglycemia and between TGF-β2 and vitreous hemorrhage in proliferative diabetic retinopathy eyes, which suggests that IL-6 and TGF-β2 play important roles in the pathogenesis of diabetic retinopathy.

投稿截止日期99年10月1日