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J. Biol. Chem., Vol. 278, Issue 29, 26480-26487, July 18, 2003

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Macrophage Endothelial Nitric-oxide Synthase Autoregulates Cellular Activation and Pro-inflammatory Protein Expression^*

Linda Connelly  , Aaron T. Jacobs , Miriam Palacios-Callender ¶, Salvador Moncada ¶ and Adrian J. Hobbs ¶ ||

From the Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, California 90095 and ^¶Wolfson Institute for Biomedical Research, University College London, London WC1E 6AE, United Kingdom

Expression of inducible nitric-oxide (NO) synthase (iNOS) and "high-output" production of NO by macrophages mediates many cytotoxic actions of these immune cells. However, macrophages have also been shown to express a constitutive NOS isoform, the function of which remains obscure. Herein, bone marrow-derived macrophages (BMDMØs) from wild-type and endothelial NOS (eNOS) knock-out (KO) mice have been used to assess the role of this constitutive NOS isoform in the regulation of macrophage activation. BMDMØs from eNOS KO animals exhibited reduced nuclear factor-B activity, iNOS expression, and NO production after exposure to lipopolysaccharide (LPS) as compared with cells derived from wild-type mice. Soluble guanylate cyclase (sGC) was identified in BMDMØs at a mRNA and protein level, and activation of cells with LPS resulted in accumulation of cyclic GMP. Moreover, the novel non-NO-based sGC activator, BAY 41-2272, enhanced BMDMØ activation in response to LPS, and the sGC inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one attenuated activation. These observations provide the first demonstration of a pathophysiological role for macrophage eNOS in regulating cellular activation and suggest that NO derived from this constitutive NOS isoform, in part via activation of sGC, is likely to play a pivotal role in the initiation of an inflammatory response.

Received for publication, March 4, 2003 , and in revised form, May 6, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Wellcome Trust International Prize Traveling Research Fellowship.

^|| Recipient of a Wellcome Trust Senior Fellowship in Basic Biomedical Sciences. To whom correspondence should be addressed: Wolfson Institute for Biomedical Research, University College London, Cruciform Bldg., Gower St., London WC1E 6AE, United Kingdom. Tel.: 44-(0)20-7679-6611; Fax: 44-(0)20-7813-2846; E-mail: a.hobbs{at}ucl.ac.uk.

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