The benzoxathiolone LYR-71 down-regulates interferon-γ-inducible pro-inflammatory genes by uncoupling tyrosine phosphorylation of STAT-1 in macrophages

E. Y. Chung, B. H. Kim, I. J. Lee, E. Roh, S. J. Oh, J. A. Kwak, Y. R. Lee, B. Ahn, S. Y. Nam, S. B. Han, Y. Kim

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1 Scopus citations

Abstract

Background and purpose: Benzoxathiolone derivatives have shown anti-inflammatory and immunomodulatory potential in acne and psoriatic disorders. However, little is known about the molecular basis for these pharmacological effects. In this study, we decided to investigate the anti-inflammatory actions of a benzoxathiolone derivative LYR-71, 6-methyl-2-propylimino-6,7-dihydro-5H-benzo[1,3]oxathiol-4-one, in interferon (IFN)-γ-activated macrophages. Experimental approach: RAW 264.7 macrophages or primary macrophages, derived from bone marrow of C3H/HeJ mice, were stimulated with IFN-γ in the presence of LYR-71. Nitric oxide (NO) or chemokine production was measured by Griess reaction or enzyme-linked immunosorbent assay. RAW 264.7 cells were used to examine the molecular mechanisms of LYR-71 in modulating IFN-γ-induced inflammatory responses. Key results: LYR-71 down-regulated IFN-γ-induced transcription of inducible NO synthase, IFN-γ-inducible protein-10 and the monokine induced by IFN-γ genes in macrophages. This effect was mediated by uncoupling tyrosine phosphorylation of the signal transducer and activator of transcription (STAT)-1 in response to IFN-γ. LYR-71 directly inhibited the in vitro catalytic activity of Janus kinase (JAK)-2. Further, the inhibitory actions of LYR-71 on IFN-γ-induced STAT-1 phosphorylation and NO production were consistently abolished in the presence of peroxyvanadate, implying another target dependent on protein tyrosine phosphatase. Conclusions and implications: Taken together, LYR-71 could restrain IFN-γ-induced inflammatory responses through uncoupling the tyrosine phosphorylation of STAT-1, an activation index of JAK-STAT-1 signalling, in macrophages. These results may provide a molecular mechanism underlying anti-inflammatory actions shown by benzoxathiolone derivatives.

Original languageEnglish (US)
Pages (from-to)1971-1981
Number of pages11
JournalBritish Journal of Pharmacology
Volume158
Issue number8
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

Keywords

  • Anti-inflammatory action
  • Benzoxathiolone derivative
  • Chemokine
  • IFN-γ
  • Janus kinase
  • Macrophages
  • Nitric oxide
  • STAT-1

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