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Inhibition of cytokine-induced JAK-STAT signalling pathways by an endonuclease inhibitor aurintricarboxylic acid.
- Source :
-
British journal of pharmacology [Br J Pharmacol] 2002 Dec; Vol. 137 (7), pp. 1011-20. - Publication Year :
- 2002
-
Abstract
- 1. Inducible nitric oxide (iNOS) is thought to involve in host defence and tissue damage in inflammatory loci. In previous study, we have found that the endonuclease inhibitor aurintricarboxylic acid (ATA) can protect macrophages from cell death induced by bacterial lipopolysaccharide. This action is through the interruption with signalling pathways for NF-kappa B and AP-1 activation, and thus iNOS expression. In this study we have addressed the effects of ATA on JAK-STAT signalling pathways. 2. In murine RAW 264.7 macrophages, IFN-gamma-mediated NO production and iNOS expression were concentration-dependently reduced by the presence of 3-100 micro M ATA. 3. IFN-gamma-induced STAT1 activation, as assessed from its tyrosine phosphorylation, nuclear translocation, binding to specific DNA response element and evoked IRF-1 reporter gene assay, were concomitantly inhibited by ATA. However, ATA did not alter IFN-gamma binding to RAW 264.7 cells. 4. The activities of JAK1 and JAK2, the upstream kinases essential for STAT1 signalling in response to IFN-gamma, were also reduced by ATA. 5. Moreover, IL-4, IL-10, GM-CSF and M-CSF elicited tyrosine phosphorylation of STAT3, STAT5 and/or STAT6 in macrophages were diminished by the presence of ATA. 6. Taken together, we conclude that ATA can interfere JAK-STAT signalling pathways in response to cytokines. This action contributes to the inhibition of IFN-gamma-induced iNOS expression.
- Subjects :
- Animals
Cell Line
Dose-Response Relationship, Drug
Endonucleases antagonists & inhibitors
Enzyme Activation drug effects
Granulocyte-Macrophage Colony-Stimulating Factor pharmacology
HT29 Cells
Humans
Interferon-gamma pharmacology
Interleukin-10 pharmacology
Interleukin-4 pharmacology
Janus Kinase 1
Macrophages cytology
Macrophages drug effects
Macrophages metabolism
Nitric Oxide metabolism
Nitric Oxide Synthase genetics
Nitric Oxide Synthase metabolism
Nitric Oxide Synthase Type II
Phosphorylation drug effects
Protein Binding drug effects
RNA, Messenger drug effects
RNA, Messenger genetics
RNA, Messenger metabolism
STAT1 Transcription Factor
STAT3 Transcription Factor
STAT5 Transcription Factor
STAT6 Transcription Factor
Transcription, Genetic drug effects
Tyrosine metabolism
Aurintricarboxylic Acid pharmacology
Cytokines pharmacology
DNA-Binding Proteins metabolism
Milk Proteins
Protein-Tyrosine Kinases metabolism
Signal Transduction drug effects
Trans-Activators metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0007-1188
- Volume :
- 137
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- British journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 12429573
- Full Text :
- https://doi.org/10.1038/sj.bjp.0704955