A potential role of YC-1 on the inhibition of cytokine release in peripheral blood mononuclear leukocytes and endotoxemic mouse models.
To evaluate the anti-sepsis potential of YC-1, we have examined the effect of YC-1 on the regulation of cytokine production in human leukocytes and endotoxemic mice. The data demonstrated that YC-1 showed a preferential inhibition on proinflammatory cytokine production without inhibition of cell growth or induction of cytotoxicity in human leukocytes. On the other hand, in the septic mouse model, treatment with an intraperitoneal application of LPS caused a cumulative death within 27 hours. The post-treatment administration of YC-1 significantly increased the survival rate in endotoxemic mice. Furthermore, several mediators were detected and the data showed that YC-1 profoundly blocked LPS-induced NO as well as TNF-alpha production, and prevented lung damage by histological examination. Samples from the animal model showed that LPS-induced NF-kappaB/DNA binding activity and consequent up-regulation of iNOS expression in tissues were abolished by post-administration of YC-1. Furthermore, YC-1, by itself, did not modify cGMP content while significantly inhibit LPS-induced cGMP formation, suggesting that YC-1-mediated effect was not through a cGMP-elevating pathway. Taken together, it is evident that the post-treatment administration of YC-1 after LPS application significantly inhibits NF-kappaB activation, iNOS expression, NO over-production, and cytokine release reaction resulting in an improved survival rate in endotoxemic mice. It is suggested that YC-1 may be a potential agent for the therapeutic treatment of sepsis.
Pan
Shiow-Lin
SL
Pharmacological Institutes, College of Medicine, National Taiwan University, Taipei.
Guh
Jih-Hwa
JH
Peng
Chieh-Yu
CY
Chang
Ya-Ling
YL
Cheng
Fong-Chi
FC
Chang
Jau-Hsiang
JH
Kuo
Sheng-Chu
SC
Lee
Fang-Yu
FY
Teng
Che-Ming
CM
D000818:Animals; D015153:Blotting, Western; D006152:Cyclic GMP / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000097:blood; D006801:Humans; D007150:Immunohistochemistry; D007191:Indazoles / Q000494:pharmacology*; D007962:Leukocytes / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000166:cytology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic; D013997:Time Factors; D015854:Up-Regulation
D016207:Cytokines; D007191:Indazoles; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010975:Platelet Aggregation Inhibitors; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009569:Nitric Oxide; D004247:DNA; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D006152:Cyclic GMP