RT Journal Article
SR Electronic
T1 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
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 308
OP 315
DO 10.1124/mol.64.2.308
VO 64
IS 2
A1 Aleksi Lahti
A1 Ulla Jalonen
A1 Hannu Kankaanranta
A1 Eeva Moilanen
YR 2003
UL http://molpharm.aspetjournals.org/content/64/2/308.abstract
AB 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 κB, 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.