MolPharm

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Flamand, N.
Right arrow Articles by Borgeat, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Flamand, N.
Right arrow Articles by Borgeat, P.

Vol. 62, Issue 2, 250-256, August 2002

Cyclic AMP-Mediated Inhibition of 5-Lipoxygenase Translocation and Leukotriene Biosynthesis in Human Neutrophils

Nicolas Flamand, Marc E. Surette, Serge Picard, Sylvain Bourgoin, and Pierre Borgeat

Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du CHUQ, and Faculté de Médecine, Université Laval, Québec, Canada

5-Lipoxygenase (5-LO) catalyzes the transformation of arachidonic acid to leukotrienes (LT). In stimulated human PMN, activation of 5-LO involves calcium, p38 MAP kinase (p38) phosphorylation, and translocation of 5-LO from the cytosol to nuclear membranes containing the 5-LO activating protein (FLAP). In this study, cAMP-elevating agents such as isoproterenol, prostaglandin E2, CGS-21680 (an adenosine A2a receptor agonist), the type IV phosphodiesterase inhibitor RO 20-1724, the adenylate cyclase activator forskolin, and the Gs-protein activator cholera toxin all inhibited LT biosynthesis and 5-LO translocation to the nucleus in cytokine-primed human PMN stimulated with platelet-activating factor and in human PMN stimulated with the endomembrane Ca2+-ATPase blocker thapsigargin. Furthermore, monophosphorothioate analogs of cAMP, which activate protein kinase A (PKA), also inhibited LT biosynthesis and 5-LO translocation in stimulated cells. Treatment of PMN with CGS-21680 also prevented the phosphorylation of p38 by thapsigargin. Treatment of PMN with the PKA inhibitors H-89 and KT-5720 prevented the inhibitory effect of cAMP-elevating agents on LT biosynthesis, 5-LO translocation, and p38 phosphorylation, whereas the p38 inhibitor SB 203,580 dose-dependently inhibited arachidonic acid-induced LT biosynthesis. The 5-LO translocation was also inhibitable by the FLAP antagonist MK-0591 and correlated with LT biosynthesis in all experimental conditions tested. These results indicate that cAMP-mediated PKA activation in PMN results in the concomitant inhibition of 5-LO translocation and LT biosynthesis and support a role of p38 in the signaling pathway involved. This represents the first physiological down-regulation mechanism of 5-LO translocation in human PMN.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Lipid Res.Home page
O. Radmark and B. Samuelsson
5-Lipoxygenase: mechanisms of regulation
J. Lipid Res., April 1, 2009; 50(Supplement): S40 - S45.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
S. Farooque and T. H Lee
Aspirin sensitivity and eicosanoids
Thorax, January 1, 2008; 63(1): 2 - 4.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
V. Leone, A. di Palma, P. Ricchi, F. Acquaviva, M. Giannouli, A. M. Di Prisco, F. Iuliano, and A. M. Acquaviva
PGE2 inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation
Am J Physiol Gastrointest Liver Physiol, October 1, 2007; 293(4): G673 - G681.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
H. Allayee, J. Hartiala, W. Lee, M. Mehrabian, C. G. Irvin, D. V. Conti, and J. J. Lima
The Effect of Montelukast and Low-Dose Theophylline on Cardiovascular Disease Risk Factors in Asthmatics
Chest, September 1, 2007; 132(3): 868 - 874.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
J. Tessier, C. Green, D. Padgett, W. Zhao, L. Schwartz, M. Hughes, and E. Hewlett
Contributions of Histamine, Prostanoids, and Neurokinins to Edema Elicited by Edema Toxin from Bacillus anthracis
Infect. Immun., April 1, 2007; 75(4): 1895 - 1903.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
N. Flamand, J. Lefebvre, G. Lapointe, S. Picard, L. Lemieux, S. G. Bourgoin, and P. Borgeat
Inhibition of platelet-activating factor biosynthesis by adenosine and histamine in human neutrophils: involvement of cPLA2{alpha} and reversal by lyso-PAF
J. Leukoc. Biol., May 1, 2006; 79(5): 1043 - 1051.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
A. Fortin, D. Harbour, M. Fernandes, P. Borgeat, and S. Bourgoin
Differential expression of adenosine receptors in human neutrophils: up-regulation by specific Th1 cytokines and lipopolysaccharide
J. Leukoc. Biol., March 1, 2006; 79(3): 574 - 585.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Flamand, J. Lefebvre, M. E. Surette, S. Picard, and P. Borgeat
Arachidonic Acid Regulates the Translocation of 5-Lipoxygenase to the Nuclear Membranes in Human Neutrophils
J. Biol. Chem., January 6, 2006; 281(1): 129 - 136.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Luo, S. M. Jones, N. Flamand, D. M. Aronoff, M. Peters-Golden, and T. G. Brock
Phosphorylation by Protein Kinase A Inhibits Nuclear Import of 5-Lipoxygenase
J. Biol. Chem., December 9, 2005; 280(49): 40609 - 40616.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
A. Rossi, A. M. Acquaviva, F. Iuliano, R. Di Paola, S. Cuzzocrea, and L. Sautebin
Up-regulation of prostaglandin biosynthesis by leukotriene C4 in elicited mice peritoneal macrophages activated with lipopolysaccharide/interferon-{gamma}
J. Leukoc. Biol., October 1, 2005; 78(4): 985 - 991.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
J.-S. Cadieux, P. Leclerc, M. St-Onge, A.-A. Dussault, C. Laflamme, S. Picard, C. Ledent, P. Borgeat, and M. Pouliot
Potentiation of neutrophil cyclooxygenase-2 by adenosine: an early anti-inflammatory signal
J. Cell Sci., April 1, 2005; 118(7): 1437 - 1447.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
M. Luo, S. M. Jones, S. M. Phare, M. J. Coffey, M. Peters-Golden, and T. G. Brock
Protein Kinase A Inhibits Leukotriene Synthesis by Phosphorylation of 5-Lipoxygenase on Serine 523
J. Biol. Chem., October 1, 2004; 279(40): 41512 - 41520.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
S. Grenier, N. Flamand, J. Pelletier, P. H. Naccache, P. Borgeat, and S. G. Bourgoin
Arachidonic acid activates phospholipase D in human neutrophils; essential role of endogenous leukotriene B4 and inhibition by adenosine A2A receptor engagement
J. Leukoc. Biol., April 1, 2003; 73(4): 530 - 539.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. M. Jones, M. Luo, M. Peters-Golden, and T. G. Brock
Identification of Two Novel Nuclear Import Sequences on the 5-Lipoxygenase Protein
J. Biol. Chem., March 14, 2003; 278(12): 10257 - 10263.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
H. Harizi, M. Juzan, J.-F. Moreau, and N. Gualde
Prostaglandins Inhibit 5-Lipoxygenase-Activating Protein Expression and Leukotriene B4 Production from Dendritic Cells Via an IL-10-Dependent Mechanism
J. Immunol., January 1, 2003; 170(1): 139 - 146.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Pharmacol.Home page
T. D. Bigby
The Yin and the Yang of 5-Lipoxygenase Pathway Activation
Mol. Pharmacol., August 1, 2002; 62(2): 200 - 202.
[Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2002 by the American Society for Pharmacology and Experimental Therapeutics