Control of nitric oxide production by endogenous TGF‐β 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‐β 1 (TGF‐β 1 ) suppresses expression of the inducible form of nitric oxide synthase (iNOS). In this study, we examined the effects of exogenous and endogenous TGF‐β 1 on retinal pigment epithelial (RPE) cells and resident peritoneal macrophages ex vivo using cells from TGF‐β 1 null (TGF‐β 1 ‐/‐ ) mice or age‐matched wild‐type (TGF‐β 1 +/+ ) or heterozygous (TGF‐β 1 +/‐ ) littermates. RPE cells from both TGF‐β 1 ‐/‐ mice and TGF‐β 1 +/+ littermates produced NO and were immunocytochemically positive for iNOS protein only following treatment with interferon‐γ (IFN‐γ) and bacterial lipopolysaccharide (LPS); however, RPE cells from TGF‐β 1 ‐/‐ mice produced 40% more NO than cells from TGF‐β 1 +/+ mice. In contrast, resident peritoneal macrophages from both TGF‐β 1 +/+ and TGF‐β 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‐γ, resulting in detectable levels of NO. Macrophages from TGF‐β 1 +/+ mice appeared to produce NO in a manner inversely proportional to the serum content of NO 2 ‐ and NO 3 ‐ of the mice from which the cells were obtained; no such correlation existed in TGF‐β 1 +/‐ or TGF‐β 1 ‐/‐ mice. Treatment of RPE cells or macrophages from both TGF‐β 1 +/+ and TGF‐β 1 ‐/‐ mice with exogenous TGF‐β 1 decreased both iNOS protein and NO production. These findings demonstrate a novel role of endogenous TGF‐β 1 in coupling systemic NO production to the production of NO by macrophages, and demonstrate that endogenous and exogenous TGF‐β 1 can act differently to suppress NO production. J. Leukoc. Biol . 60: 261–270; 1996.