QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services 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 Lahti, A. Articles by Moilanen, E. Search for Related Content PubMed PubMed Citation Articles by Lahti, A. Articles by Moilanen, E.

c-Jun NH₂-Terminal Kinase Inhibitor Anthra(1,9-cd)pyrazol-6(2H)-one Reduces Inducible Nitric-Oxide Synthase Expression by Destabilizing mRNA in Activated Macrophages

The Immunopharmacological Research Group, University of Tampere Medical School and Tampere University Hospital, Tampere, Finland

In this study, we investigated the role of c-Jun NH₂-terminal kinase (JNK), a member of the mitogen-activated protein kinase (MAPK) family, in lipopolysaccharide (LPS)-stimulated inducible nitric-oxide synthase (iNOS) expression and nitric oxide (NO) production in J774 murine macrophages. Anthra(1,9-cd)pyrazol-6(2H)-one (SP600125), a pharmacological inhibitor of JNK, inhibited phosphorylation of c-Jun with an IC₅₀ of 5 to 10 µM. At the same concentrations, SP600125 inhibited LPS-induced iNOS protein expression and NO production. SP600125 had no effect on the activation of nuclear factor B, which is an important transcription factor for iNOS expression. SP600125 had no significant effect on iNOS mRNA levels if measured 4 h after LPS. In contrast, SP600125 reduced iNOS mRNA levels >90% when measured 8 h after LPS. These data suggest that SP600125 reduced iNOS mRNA stability, and this was confirmed in the mRNA degradation assay using actinomycin D, in which SP600125 reduced the iNOS mRNA half-life from 5 to 2 h. These results show that the JNK pathway is involved in the up-regulation of LPS-induced iNOS expression and NO production by a mechanism related to the stabilization of iNOS mRNA.

Address correspondence to: Dr. Eeva Moilanen, Medical School, FIN-33014 University of Tampere, Finland. E-mail: eeva.moilanen{at}uta.fi

This article has been cited by other articles:

				O. Sareila, M. Hamalainen, E. Nissinen, H. Kankaanranta, and E. Moilanen Orazipone Inhibits Activation of Inflammatory Transcription Factors Nuclear Factor-{kappa}B and Signal Transducer and Activator of Transcription 1 and Decreases Inducible Nitric-Oxide Synthase Expression and Nitric Oxide Production in Response to Inflammatory Stimuli J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 858 - 866. [Abstract] [Full Text] [PDF]

				R. Korhonen, K. Linker, A. Pautz, U. Forstermann, E. Moilanen, and H. Kleinert Post-Transcriptional Regulation of Human Inducible Nitric-Oxide Synthase Expression by the Jun N-terminal Kinase Mol. Pharmacol., May 1, 2007; 71(5): 1427 - 1434. [Abstract] [Full Text] [PDF]

				C. LaRosa and S. M. Downs Meiotic Induction by Heat Stress in Mouse Oocytes: Involvement of AMP-Activated Protein Kinase and MAPK Family Members Biol Reprod, March 1, 2007; 76(3): 476 - 486. [Abstract] [Full Text] [PDF]

				B. Zhao, J. Song, R. W. St. Clair, and S. Ghosh Stable overexpression of human macrophage cholesteryl ester hydrolase results in enhanced free cholesterol efflux from human THP1 macrophages Am J Physiol Cell Physiol, January 1, 2007; 292(1): C405 - C412. [Abstract] [Full Text] [PDF]

				M. Bergeron and M. Olivier Trypanosoma cruzi-Mediated IFN-{gamma}-Inducible Nitric Oxide Output in Macrophages Is Regulated by iNOS mRNA Stability J. Immunol., November 1, 2006; 177(9): 6271 - 6280. [Abstract] [Full Text] [PDF]

				V. A. Dennis, A. Jefferson, S. R. Singh, F. Ganapamo, and M. T. Philipp Interleukin-10 Anti-Inflammatory Response to Borrelia burgdorferi, the Agent of Lyme Disease: a Possible Role for Suppressors of Cytokine Signaling 1 and 3. Infect. Immun., October 1, 2006; 74(10): 5780 - 5789. [Abstract] [Full Text] [PDF]

				M. T. Pritchard, Z. Li, and E. A. Repasky Nitric oxide production is regulated by fever-range thermal stimulation of murine macrophages J. Leukoc. Biol., September 1, 2005; 78(3): 630 - 638. [Abstract] [Full Text] [PDF]

				C.-H. Leung, S. P. Grill, W. Lam, Q.-B. Han, H.-D. Sun, and Y.-C. Cheng Novel Mechanism of Inhibition of Nuclear Factor-{kappa}B DNA-Binding Activity by Diterpenoids Isolated from Isodon rubescens Mol. Pharmacol., August 1, 2005; 68(2): 286 - 297. [Abstract] [Full Text] [PDF]

				J. Chen, Y. Yan, J. Li, Q. Ma, G. D. Stoner, J. Ye, and C. Huang Differential requirement of signal pathways for benzo[a]pyrene (B[a]P)-induced nitric oxide synthase (iNOS) in rat esophageal epithelial cells Carcinogenesis, June 1, 2005; 26(6): 1035 - 1043. [Abstract] [Full Text] [PDF]

				S. Werber, I. Shalit, I. Fabian, G. Steuer, T. Weiss, and H. Blau Moxifloxacin inhibits cytokine-induced MAP kinase and NF-{kappa}B activation as well as nitric oxide synthesis in a human respiratory epithelial cell line J. Antimicrob. Chemother., March 1, 2005; 55(3): 293 - 300. [Abstract] [Full Text] [PDF]

				T. Matsuda, K. Ferreri, I. Todorov, Y. Kuroda, C. V. Smith, F. Kandeel, and Y. Mullen Silymarin Protects Pancreatic {beta}-Cells against Cytokine-Mediated Toxicity: Implication of c-Jun NH2-Terminal Kinase and Janus Kinase/Signal Transducer and Activator of Transcription Pathways Endocrinology, January 1, 2005; 146(1): 175 - 185. [Abstract] [Full Text] [PDF]

				R. Medeiros, D. A. Cabrini, J. Ferreira, E. S. Fernandes, M. A.S. Mori, J. B. Pesquero, M. Bader, M. C.W. Avellar, M. M. Campos, and J. B. Calixto Bradykinin B1 Receptor Expression Induced by Tissue Damage in the Rat Portal Vein: A Critical Role for Mitogen-Activated Protein Kinase and Nuclear Factor-{kappa}B Signaling Pathways Circ. Res., May 28, 2004; 94(10): 1375 - 1382. [Abstract] [Full Text] [PDF]