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© The Rockefeller University Press, 0021-9525/1999//427 $5.00
The Journal of Cell Biology, Volume 144, Number 3, , 1999 427-434

Regular Articles

Arginase II Downregulates Nitric Oxide (NO) Production and Prevents NO-mediated Apoptosis in Murine Macrophage-derived RAW 264.7 Cells



Tomomi Gotoh and Masataka Mori

Department of Molecular Genetics, Kumamoto University School of Medicine, Kumamoto 862-0976, Japan

Excess nitric oxide (NO) induces apoptosis of some cell types, including macrophages. As NO is synthesized by NO synthase (NOS) from arginine, a common substrate of arginase, these two enzymes compete for arginine. There are two known isoforms of arginase, types I and II. Using murine macrophage-like RAW 264.7 cells, we asked if the induction of arginase II would downregulate NO production and hence prevent apoptosis. When cells were exposed to lipopolysaccharide (LPS) and interferon-{gamma} (IFN-{gamma}), the inducible form of NOS (iNOS) was induced, production of NO was elevated, and apoptosis followed. When dexamethasone and cAMP were further added, both iNOS and arginase II were induced, NO production was much decreased, and apoptosis was prevented. When the cells were transfected with an arginase II expression plasmid and treated with LPS/IFN-{gamma}, some cells were rescued from apoptosis. An arginase I expression plasmid was also effective. On the other hand, transfection with the arginase II plasmid did not prevent apoptosis when a NO donor SNAP or a high concentration (12 mM) of arginine was added. These results indicate that arginase II prevents NO-dependent apoptosis of RAW 264.7 cells by depleting intracellular arginine and by decreasing NO production.

Key Words: arginase • NO • NO synthase • apoptosis • arginine

Abbreviations used in this paper: carboxy-PTIO, 2-(4-carboxyphenyl)- 4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide; Dex, dexamethasone; IFN-{gamma}, interferon-{gamma}; iNOS, inducible NO synthase; LPS, lipopolysaccharide; NO, nitric oxide; NOS, NO synthase; SNAP, S-nitroso-N-acetyl-DL-penicillamine.

Address correspondence to Dr. Masataka Mori, Department of Molecular Genetics, Kumamoto University School of Medicine, Kuhonji 4-24-1, Kumamoto 862-0976, Japan. Tel.: 81-96-373-5140. Fax: 81-96-373-5145. E-mail: masa{at}gpo.kumamoto-u.ac.jp


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