The benzoxathiolone LYR-71 down-regulates interferon-gamma-inducible pro-inflammatory genes by uncoupling tyrosine phosphorylation of STAT-1 in macrophages.
Br J Pharmacol
; 158(8): 1971-81, 2009 Dec.
Article
de En
| MEDLINE
| ID: mdl-19922538
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)-gamma-activated macrophages. EXPERIMENTALAPPROACH:
RAW 264.7 macrophages or primary macrophages, derived from bone marrow of C3H/HeJ mice, were stimulated with IFN-gamma 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-gamma-induced inflammatory responses. KEYRESULTS:
LYR-71 down-regulated IFN-gamma-induced transcription of inducible NO synthase, IFN-gamma-inducible protein-10 and the monokine induced by IFN-gamma 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-gamma. LYR-71 directly inhibited the in vitro catalytic activity of Janus kinase (JAK)-2. Further, the inhibitory actions of LYR-71 on IFN-gamma-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-gamma-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.
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Composés hétérocycliques bicycliques
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Facteur de transcription STAT-1
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Imines
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Macrophages
Limites:
Animals
Langue:
En
Journal:
Br J Pharmacol
Année:
2009
Type de document:
Article