Inhibition of cytokine-induced JAK-STAT signalling pathways by an endonuclease inhibitor aurintricarboxylic acid

Ching Wen Chen, Yee Chao, Ying Hsin Chang, Ming Jen Hsu, Wan Wan Lin

Research output: Contribution to journalArticle

32 Citations (Scopus)

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-κB 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-γ-mediated NO production and iNOS expression were concentration-dependently reduced by the presence of 3-100 μM ATA. 3. IFN-γ-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-γ binding to RAW 264.7 cells. 4. The activities of JAK1 and JAK2, the upstream kinases essential for STAT1 signalling in response to IFN-γ, 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-γ-induced iNOS expression.

Original languageEnglish
Pages (from-to)1011-1020
Number of pages10
JournalBritish Journal of Pharmacology
Volume137
Issue number7
DOIs
Publication statusPublished - Dec 2002
Externally publishedYes

Keywords

  • Aurintricarboxylic acid
  • Cytokines
  • iNOS
  • Interferon-γ
  • JAK
  • STAT

ASJC Scopus subject areas

  • Pharmacology

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