HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 29, 29895-29901, July 16, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/29/29895    most recent M312768200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Palomba, L. Articles by Cantoni, O. Search for Related Content PubMed PubMed Citation Articles by Palomba, L. Articles by Cantoni, O. Social Bookmarking                      What's this?

Inhibition of Nitric-oxide Synthase-I (NOS-I)-dependent Nitric Oxide Production by Lipopolysaccharide plus Interferon- Is Mediated by Arachidonic Acid

EFFECTS ON NFB ACTIVATION AND LATE INDUCIBLE NOS EXPRESSION^*

Letizia Palomba, Tiziana Persichini¶, Valeria Mazzone¶, Marco Colasanti¶||, and Orazio Cantoni

From the Istituto di Farmacologia e Farmacognosia, Università di Urbino "Carlo Bo," Via S. Chiara 27, 61029 Urbino, Italy and the ^¶Dipartimento di Biologia, Università di Roma Tre, Viale Marconi 446, 00146 Roma, Italy

Previous results have indicated that lipopolysaccharide (LPS) plus interferon- (IFN) inhibits nitric-oxide synthase (NOS)-I activity in glial cells. We report here that arachidonic acid (AA) plays a pivotal role in this response, which was consistently reproduced in different glial cell lines and in primary rat astrocytes. This notion was established using pharmacological inhibitors of phospholipase A₂ (PLA₂), cytosolic PLA₂ (cPLA₂) antisense oligonucleotides, and AA add-back experiments. This approach not only allowed the demonstration that AA promotes inhibition of NOS-I activity but also produced novel experimental evidence that LPS/IFN itself is a potential stimulus for NOS-I. Indeed, LPS/IFN fails to generate nitric oxide (NO) via NOS-I activation simply because it activates the AA-dependent signal that impedes NOS-I activity. Otherwise, LPS/IFN promotes NO formation, sensitive to exogenous AA, in cells in which cPLA₂ is pharmacologically inhibited or genetically depleted. Because NO suppresses the NFB-dependent NOS-II expression, inactivation of NOS-I by the LPS/IFN-induced AA pathway provides optimal conditions for NFB activation and subsequent NOS-II expression. Inhibition of cPLA₂ activity, while reducing the availability of AA, consistently inhibited NFB activation and NOS-II mRNA induction and delayed NO formation. These responses were promptly reestablished by addition of exogenous AA. Finally, we have demonstrated that the LPS/IFN-dependent tyrosine phosphorylation of NOS-I and inhibition of its activity are mediated by endogenous AA.

Received for publication, November 21, 2003 , and in revised form, May 11, 2004.

^* This work was supported by grants from Ministero dell'Università e della Ricerca Scientifica e Tecnologica, Progetti di Ricerca di Interesse Nazionale (to O. C. and M. C.). 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.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed. Tel.: 39-06-55176338; Fax: 39-06-55176321; E-mail: colasant{at}uniroma3.it.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. Keen, A.-C. Olin, A. Edentoft, E. Gronowitz, and B. Strandvik Airway Nitric Oxide in Patients With Cystic Fibrosis Is Associated With Pancreatic Function, Pseudomonas Infection, and Polyunsaturated Fatty Acids Chest, June 1, 2007; 131(6): 1857 - 1864. [Abstract] [Full Text] [PDF]

				S. Mizuno and T. Nakamura Prevention of Neutrophil Extravasation by Hepatocyte Growth Factor Leads to Attenuations of Tubular Apoptosis and Renal Dysfunction in Mouse Ischemic Kidneys Am. J. Pathol., June 1, 2005; 166(6): 1895 - 1905. [Abstract] [Full Text] [PDF]