TUMOR-NECROSIS-FACTOR AND NITRIC-OXIDE PRODUCTION BY RETINAL MULLER GLIAL-CELLS FROM RATS EXHIBITING INHERITED RETINAL DYSTROPHY

The primary cause of the inherited retinal dystrophy observed in Royal College of Surgeons (RCS) rats is located in the retinal pigmented ep ithelium, which is unable to phagocytize photoreceptor outer segments. We have demonstrated here that retinal Muller glial (RMG) cells obtai ned from RCS dystrophic rats and stimulated in vitro with lipopolysacc haride (LPS) and interferon-gamma (IFN-gamma) accumulated higher level s of tumor necrosis factor (TNF) and inducible nitric oxide synthase ( NOS II) mRNA and released in culture supernatants significantly higher amounts of TNF and nitrite compared to cells derived from nondystroph ic controls. The TNF and NOS II mRNA expression and TNF and nitrite sy nthesis induced in RMG cells from both strains by LPS + IFN-gamma was significantly prevented by including transforming growth factor-beta ( TGF-beta) in the culture medium. Coincubation of the stimulants with a n inhibitor of NOS II, N-G-monomethyl-L-arginine (L-NMMA), while inhib iting nitrite synthesis, induced an increase of TNF production in supe rnatants from RMG cells without increasing TNF mRNA levels. The retina l dystrophy observed in RCS dystrophic rats could result from an abnor mal susceptibility of RMG cells from RCS dystrophic rats to produce TN F and NO in response to stimulants. Administration of the immunomodula tory cytokine TGF-beta or inhibitors of NOS II would provide additiona l research avenues for photoreceptor rescue. (C) 1997 Wiley-Liss, Inc.