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


METHODS
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.


RESULTS
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
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.
Chung
E-Y
EY
College of Pharmacy, Chungbuk National University, Cheongju, Korea.
Kim
B-H
BH
Lee
I-J
IJ
Roh
E
E
Oh
S-J
SJ
Kwak
J-A
JA
Lee
Y-R
YR
Ahn
B
B
Nam
S-Y
SY
Han
S-B
SB
Kim
Y
Y
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D007097:Imines / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D007371:Interferon-gamma / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009569:Nitric Oxide / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor / Q000187:drug effects* / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007097:Imines; C530478:LYR 71; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D009569:Nitric Oxide; D014443:Tyrosine; D007371:Interferon-gamma