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J. Biol. Chem., Vol. 276, Issue 36, 34051-34058, September 7, 2001

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Protein Tyrosine Nitration in Cytokine-activated Murine Macrophages
INVOLVEMENT OF A PEROXIDASE/NITRITE PATHWAY RATHER THAN PEROXYNITRITE^*

Silvia Pfeiffer, Achim Lass, Kurt Schmidt, and Bernd Mayer^§

From the Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria

Peroxynitrite, formed in a rapid reaction of nitric oxide (NO) and superoxide anion radical (O₂), is thought to mediate protein tyrosine nitration in various inflammatory and infectious diseases. However, a recent in vitro study indicated that peroxynitrite exhibits poor nitrating efficiency at biologically relevant steady-state concentrations (Pfeiffer, S., Schmidt, K., and Mayer, B. (2000) J. Biol. Chem. 275, 6346-6352). To investigate the molecular mechanism of protein tyrosine nitration in intact cells, murine RAW 264.7 macrophages were activated with immunological stimuli, causing inducible NO synthase expression (interferon- in combination with either lipopolysaccharide or zymosan A), followed by the determination of protein-bound 3-nitrotyrosine levels and release of potential triggers of nitration (NO, O₂, H₂O₂, peroxynitrite, and nitrite). Levels of 3-nitrotyrosine started to increase at 16-18 h and exhibited a maximum at 20-24 h post-stimulation. Formation of O₂ was maximal at 1-5 h and decreased to base line 5 h after stimulation. Release of NO peaked at ~6 and ~9 h after stimulation with interferon-/lipopolysaccharide and interferon-/zymosan A, respectively, followed by a rapid decline to base line within the next 4 h. NO formation resulted in accumulation of nitrite, which leveled off at about 50 µM 15 h post-stimulation. Significant release of peroxynitrite was detectable only upon treatment of cytokine-activated cells with phorbol 12-myristate-13-acetate, which led to a 2.2-fold increase in dihydrorhodamine oxidation without significantly increasing the levels of 3-nitrotyrosine. Tyrosine nitration was inhibited by azide and catalase and mimicked by incubation of unstimulated cells with nitrite. Together with the striking discrepancy in the time course of NO/O₂ release versus 3-nitrotyrosine formation, these results suggest that protein tyrosine nitration in activated macrophages is caused by a nitrite-dependent peroxidase reaction rather than peroxynitrite.

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