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L-Arginine-dependent Reactive Nitrogen Intermediates as Mediators of Tumor Cell Killing by Activated Macrophages¹

Immunobiology Research Group, Institute of Immunology and Virology, University of Zurich, Birchstrasse 95, CH-8050 Zurich, Switzerland

The capacities of lymphokines and of various microbes to induce in a pure population of bone marrow-derived mononuclear phagocytes tumoricidal activity and/or the production of L-arginine-dependent reactive nitrogen intermediates, measured by the release of nitrite, were comparatively assessed. These parameters were found to be closely correlated in a variety of experimental situations, i.e., enhanced by a surplus of L-arginine and abrogated by N-monomethyl-L-arginine, a selective inhibitor of L-arginine-dependent effector mechanisms. In other macrophage/tumor cell combinations, such correlation was less obvious or not at all detectable, suggesting that, in these models, L-arginine-dependent reactive nitrogen intermediates are not or not alone responsible for the mediation of tumoricidal activity by activated macrophages. Collectively, the present findings suggest that the mechanism of tumor cell killing by activated macrophages may differ, depending on the tumor cell type and the pathway of macrophage activation. Among the various effector mechanisms considered to be involved in tumor cell killing by activated macrophages, L-arginine-dependent reactive nitrogen intermediates appear to hold a major role.

¹ This study was supported by the Swiss National Science Foundation (Grant 3.336.86) and the Kanton Zurich. Part of this work was done in fulfillment of the requirements for the M.D. degree for M. G. at the Faculty of Medicine, University of Zurich, Zurich, Switzerland.

² To whom requests for reprints should be addressed.

Received 5/25/89. Revised 11/13/89. Accepted 11/27/89.

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