1. Inhibition of cytokine-induced JAK-STAT signalling pathways by an endonuclease inhibitor aurintricarboxylic acid.
- Author
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Chen CW, Chao Y, Chang YH, Hsu MJ, and Lin WW
- 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
- 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.
- Published
- 2002
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