CONTROL OF NITRIC-OXIDE PRODUCTION BY ENDOGENOUS TGF-BETA(1) AND SYSTEMIC NITRIC-OXIDE IN RETINAL-PIGMENT EPITHELIAL-CELLS AND PERITONEAL-MACROPHAGES

Both in vivo and in vitro experiments demonstrate that transforming gr owth factor-beta(1) (TGF-beta(1)) suppresses expression of the inducib le form of nitric oxide synthase (iNOS), In this study, we examined th e effects of exogenous and endogenous TGF-beta(1) on retinal pigment e pithelial (RPE) cells and resident peritoneal macrophages ex vivo usin g cells from TGF-beta(1) null (TGF-beta(1)(-/-)) mice or age-matched w ild-type (TGF-beta(1)(+/+)) or heterozygous (TGF-beta(1)(+/-)) litterm ates. RPE cells from both TGF-beta(1)(+/-) mice and TGF-beta(1)(+/+) l ittermates produced NO and were immunocytochemically positive for iNOS protein only following treatment with interferon-gamma (IFN-gamma) an d bacterial lipopolysaccharide (LPS); however, RPE cells from TGF-beta (1)(-/-) mice produced 40% more NO than cells from TGF-beta(1)(+/+) mi ce, In contrast, resident peritoneal macrophages from both TGF-beta(1) (+/+) and TGF-beta(1)(-/-) mice expressed iNOS protein without stimula tion and in the absence of detectable production of NO, The expression of iNOS was increased by treatment with IFN-gamma, resulting in detec table levels of NO, Macrophages from TGF-beta(1)(+/+) mice appeared to produce NO in a manner inversely proportional to the serum content of NO2- and NO3- of the mice from which the cells were obtained; no such correlation existed in TGF-beta(1)(+/-) or TGF-beta(1)(-/-) mice, Tre atment of RPE cells or macrophages from both TGF-beta(1)(+/+) and TGF- beta(1)(-/-) mice with exogenous TGF-beta(1) decreased both iNOS prote in and NO production, These findings demonstrate a novel role of endog enous TGF-beta(1) in coupling systemic NO production to the production of NO by macrophages, and demonstrate that endogenous and exogenous T GF-beta(1) can act differently to suppress NO production.