Bis-(3-hydroxyphenyl) diselenide inhibits LPS-stimulated iNOS and COX-2 expression in RAW 264.7 macrophage cells through the NF-kappaB inactivation.
OBJECTIVE
Previously, we reported that diaryl diselenide compounds have strong inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in macrophages. In this study, we investigated the molecular mechanisms underlying NO suppression and prostaglandin E(2) (PGE(2)) production by diaryl diselenide compounds, bis-(2-hydroxyphenyl) diselenide (DSE-A), bis-(3-hydroxyphenyl) diselenide (DSE-B), bis-(4-hydroxyphenyl) diselenide (DSE-C), dipyridyl diselenide (DSE-D) and diphenyl diselenide (DSE-E).


METHODS
The effect of these compounds on NO suppression and PGE(2) production was investigated in RAW 264.7 macrophages.


RESULTS
Our data indicate that of the above, DSE-B most potently inhibits NO and PGE(2) production, and that it also significantly reduces the releases of tumour necrosis factor (TNF)-alpha, interleukin(IL)-1beta and IL-6. Consistent with these observations, DSE-B also reduced the protein levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), and the mRNA levels of iNOS, COX-2, TNF-alpha, IL-1beta and IL-6. Furthermore, DSE-B inhibited LPS-induced nuclear factor-kappaB (NF-kappaB) activation, which was associated with the prevention of the inhibitor kappaB-alpha (IkappaB-alpha) degradation and a subsequent reduction in nuclear p65 protein levels.


CONCLUSIONS
Taken together, our data suggest that the anti-inflammatory properties of DSE-B are due to reduction in the expression of iNOS, COX-2, TNF-alpha, IL-1beta and IL-6 through the down-regulation of NF-kappaB binding activity.
Shin
Kyung-Min
KM
College of Pharmacy, Kyung-Hee University, Dongdaemun-gu, Seoul, South Korea.
Shen
Liulan
L
Park
Seung Jae
SJ
Jeong
Jin-Hyun
JH
Lee
Kyung-Tae
KT
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018036:Selenium Compounds / Q000494:pharmacology*; D050863:Synaptotagmin I / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D008070:Lipopolysaccharides; D019402:Macrophage Inflammatory Proteins; D016328:NF-kappa B; D016566:Organoselenium Compounds; D010636:Phenols; D012333:RNA, Messenger; D018036:Selenium Compounds; D050863:Synaptotagmin I; C541028:bis(3-hydroxyphenyl) diselenide; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2; D015232:Dinoprostone