Pergamon Progress in Growth Factor Research, Vol. 5. pp. 341 35l, 1994 Copyright © 1995 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0955-2235/94 $26.00 0955-2235(94)00004-2 CONTROL OF NITRIC OXIDE SYNTHASE EXPRESSION BY TRANSFORMING GROWTH FACTOR-#: IMPLICATIONS FOR HOMEOSTASIS Yoram Vodovotz* and Christian Bogdant *Laboratory of Chemoprevention, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, U.S.A. tlnstitut ffir klinische Mikrobiologie, Universit~it Erlangen, Wasserturmstra/3e 3, D-91054, Erlangen, Germany Production of nitric oxide (NO) can be stimulated by inflammatory cytokines and bacterial lipopolysaecharide (LPS) in mammalian cells via an inducible nitric oxide synthase (iNOS). Conversely, the transforming growth factor-fls (TGF-[3s) suppress NO production by reducing iNOS expression. Production of NO leads to disparate consequences, some beneficial and some damaging to the host, depending on the cell and context in which iNOS is induced. The TGF-[3s counter these NO-mediated processes in macrophages, cardiac myocytes, smooth muscle cells, bone marrow cells, and retinal pigment epithelial cells. Autocrine or paracrine production of TGF-fl may thus serve as a physiological counterbalance for iNOS expression, a mechanism which may be subverted by pathogens and tumors for their own survival. A greater under- standing of the mechanisms and consequences of NO and TGF-~ production may lead to effective therapeutic strategies in various diseases. Keywords: Nitric oxide, TGF-~, macrophage, cardiac myocyte, retinal pigment epithelial cell. INTRODUCTION Production of nitric oxide (NO) was originally described almost a decade ago in mouse macrophages [1]. Since then, the synthesis of NO has been reported in many other cell types, leading to the suggestion that all cells, presumably during inflam- matory reactions, can produce this highly reactive molecule. In mammalian cells there are three isoforms of the homodimeric enzyme, nitric oxide synthase (NOS) Acknowledgements--The authors would like to thank Carl Nathan (Cornell University Medical College, New York, NY) for his guidance and inspiration throughout the years of joint research on the control of nitric oxide production, and Michael Sporn, Anita Roberts, and members of the Laboratory of Chemoprevention (National Cancer Institute, Bethesda, MD) for critical reading of this manuscript. Preparation of this manuscript and conduct of some of the studies reviewed herein were supported in part by the Deutsche Forschungsgemeinschaft (grant Bo 996/1-1) and by the National Institutes of Health (grant CA43610). 341