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Published online before print April 1, 2004

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1003459

Received for publication October 7, 2003.
Revised February 2, 2004.
Accepted for publication February 9, 2004.

Article

A new role for monoamine oxidases in the modulation of macrophage-inducible nitric oxide synthase gene expression

Antonio Vega ^*, Pedro Chacón ^*, Javier Monteseirín ^*, Rajaa El Bekay , Moisés Álvarez , Gonzalo Alba , José Conde ^*, José Martín-Nieto , Francisco J. Bedoya , Elizabeth Pintado , and Francisco Sobrino ^@

Departamento de Bioquímica Médica y Biología Molecular, Universidad de Sevilla, Spain; *Servicio de Inmunología y Alergia, Hospital Universitario Virgen Macarena, Sevilla, Spain; Clínica Sagrado Corazón, Sevilla, Spain; and Departamento de Fisiología, Genética y Microbiología, Facultad de Ciencias, Universidad de Alicante, Spain

^@ To whom correspondence should be addressed. E-mail: fsobrino{at}us.es.

	Abstract

This report focuses on the modulatory role of endogenous H₂O₂ on lipopolysaccharide (LPS)/interferon- (IFN-)-induced inducible nitric oxide synthase (NOS2) gene expression in rat peritoneal macrophages. Exogenously added H₂O₂ was initially found to inhibit the synthesis of NOS2, which prompted us to assess the effect of the activity of monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) as H₂O₂-forming enzymes on NOS2 gene expression. In the presence of their substrates, tyramine for MAO and benzylamine for SSAO, intracellular synthesis of H₂O₂ took place with concomitant inhibition of LPS/IFN--induced NOS2 protein synthesis, as detected by Western blotting, flow cytometry, and immunofluorescence microscopy analyses. Pargyline and semicarbazide, specific inhibitors of MAO and SSAO, respectively, canceled this negative effect of MAO substrates on NOS2 expression. In the presence of Fe²⁺ and Cu²⁺ ions, inhibition of NOS2 expression was enhanced, suggesting the participation in this regulation of species derived from Fenton chemistry. In addition, the negative effect of H₂O₂, generated by MAOs, was found to be exerted on NOS2 mRNA levels. These data offer a new insight in the control of NOS2 expression through the intracellular levels of H₂O₂ and other reactive oxygen species (ROS). The hypothesis can be raised that the inhibition of NOS by H₂O₂ could constitute a protective mechanism against the cytotoxic consequences of the activation of ROS-generating enzymes, thus providing a new, singular role for the MAO family of proteins.

Key Words: NOS2 • oxidative stress • H₂O₂

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