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Regulation of Transforming Growth Factor ß1 by Nitric Oxide

Radiation Biology Branch [Y. V., W. D., D. A. W.], and Laboratory of Cell Regulation and Carcinogenesis [L. C., S-J. K., B. R.], National Cancer Institute, Bethesda, Maryland 20892; Life Sciences Division, Lawrence Berkeley Laboratory, Berkeley, California 94720 [H. C., M. H. B-H.]; Laboratory of Neurotoxicology, National Institute of Mental Health, Bethesda, Maryland 20892 [J. T. S.]; and Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814 [G. W. C.]

Many tumor cells or their secreted products suppress the function of tumor-infiltrating macrophages. Tumor cells often produce abundant transforming growth factor ß1 (TGF-ß1), which in addition to other immunosuppressive actions suppresses the inducible isoform of NO synthase. TGF-ß1 is secreted in a latent form, which consists of TGF-ß1 noncovalently associated with latency-associated peptide (LAP) and which can be activated efficiently by exposure to reactive oxygen species. Coculture of the human lung adenocarcinoma cell line A549 and ANA-1 macrophages activated with IFN- plus lipopolysaccharide resulted in increased synthesis and activation of latent TGF-ß1 protein by both A549 and ANA-1 cells, whereas unstimulated cultures of either cell type alone expressed only latent TGF-ß1. We investigated whether exposure of tumor cells to NO influences the production, activation, or activity of TGF-ß1. A549 human lung adenocarcinoma cells exposed to the chemical NO donor diethylamine-NONOate showed increased immunoreactivity of cell-associated latent and active TGF-ß1 in a time- and dose-dependent fashion at 24–48 h after treatment. Exposure of latent TGF-ß1 to solution sources of NO neither led to recombinant latent TGF-ß1 activation nor modified recombinant TGF-ß1 activity. A novel mechanism was observed, however: treatment of recombinant LAP with NO resulted in its nitrosylation and interfered with its ability to neutralize active TGF-ß1. These results provide the first evidence that nitrosative stress influences the regulation of TGF-ß1 and raise the possibility that NO production may augment TGF-ß1 activity by modifying a naturally occurring neutralizing peptide.

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