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 growth factor-beta(1) (TGF-beta(1)) suppresses expression of the inducible form of nitric oxide synthase (iNOS), In this study, we examined the effects of exogenous and endogenous TGF-beta(1) on retinal pigment epithelial (RPE) cells and resident peritoneal macrophages ex vivo using cells from TGF-beta(1) null (TGF-beta(1)(-/-)) mice or age-matched wild-type (TGF-beta(1)(+/+)) or heterozygous (TGF-beta(1)(+/-)) littermates. RPE cells from both TGF-beta(1)(+/-) mice and TGF-beta(1)(+/+) littermates produced NO and were immunocytochemically positive for iNOS protein only following treatment with interferon-gamma (IFN-gamma) and bacterial lipopolysaccharide (LPS); however, RPE cells from TGF-beta(1)(-/-) mice produced 40% more NO than cells from TGF-beta(1)(+/+) mice, In contrast, resident peritoneal macrophages from both TGF-beta(1)(+/+) and TGF-beta(1)(-/-) mice expressed iNOS protein without stimulation and in the absence of detectable production of NO, The expression of iNOS was increased by treatment with IFN-gamma, resulting in detectable 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, Treatment of RPE cells or macrophages from both TGF-beta(1)(+/+) and TGF-beta(1)(-/-) mice with exogenous TGF-beta(1) decreased both iNOS protein and NO production, These findings demonstrate a novel role of endogenous TGF-beta(1) in coupling systemic NO production to the production of NO by macrophages, and demonstrate that endogenous and exogenous TGF-beta(1) can act differently to suppress NO production.