TUMOR-NECROSIS-FACTOR AND NITRIC-OXIDE PRODUCTION BY RESIDENT RETINALGLIAL-CELLS FROM RATS PRESENTING HEREDITARY RETINAL DEGENERATION

The inherited retinal dystrophy observed in Royal College of Surgeons (RCS) rats is a widely used model for the study of the photoreceptor d egeneration that occurs in retinitis pigmentosa and macular degenerati on. The visual cell degeneration is accompanied by an abnormal accumul ation of microglial cells in the retina of RCS rats presenting the dys trophy. In the present study, we show that combined stimulation of RCS dystrophic retinal Muller glial (RMG) cells with interferon-gamma (IF N-gamma) and lipopolysaccharide (LPS) induced the release in culture s upernatants of significantly higher amounts of tumor necrosis factor ( TNF) and nitric oxide (NO) compared to nondystrophic congenic controls . In contrast, the levels of TNF and NO found in the supernatants from microglial cells were not significantly different in both strains. In terestingly, as shown by thymidine incorporation, microglial cells fro m RCS dystrophic rats have a prominent capacity of proliferation in cu lture medium compared to microglia isolated from RCS non dystrophic co ntrols. Incubation of RMG cells and microglia with the stereoselective inhibitor of NOS, N-G-monomethyl-L-arginine (L-NMMA), inhibited nitri te release in LPS + IFN-gamma-stimulated RMG cells and microglia. The addition of TGF-beta with LPS + IFN-gamma clearly inhibited TNF releas e in supernatants from both dystrophic and control rat RMG cells and m icroglia. While TGF-beta significantly inhibited nitrite synthesis in RMG cells, the effect on nitrite synthesis by microglia was very low. The retinal dystrophy observed in RCS dystrophic rats could result fro m an abnormal reactivity of RMG and microglial cells to release TNF an d NO in response to stimulants. The immunomodulatory cytokine TGF-beta and inhibitors of NOS could be negative regulators in the cytokine ne twork and nitrite synthesis thus interfering with the development of p hotoreceptor cell death.