Effect of thiol-containing molecule cysteamine on the induction of inducible nitric oxide synthase in hepatocytes
Effect of thiol-containing molecule cysteamine on the induction of inducible nitric oxide synthase in hepatocytes
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DOI：
10.1177/0148607107031005366
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发表时间：
2007-09-01
影响因子：
3.4
通讯作者：
Okumura, Tadayoshi
中科院分区：
文献类型：
--
作者：
Ozaki, Takashi;Kaibori, Masaki;Okumura, Tadayoshi
Background: Cysteamine, which is a known antioxidant and anti-inflammatory agent, is believed to be a key regulator of essential metabolic pathways in organisms. Cysteamine has beneficial effects in liver damaged by a variety of insults. During liver injury, inducible nitric oxide synthase (iNOS) is induced by lipopolysaccharide or proinflammatory cytokines, leading to excessive nitric oxide (NO) production. Accumulated evidence indicates that NO is an important factor associated with hepatic dysfunction. We examined whether cysteamine influences the induction of iNOS in hepatocytes. Methods: Primary cultured rat hepatocytes were treated with interleukin (IL)-1 beta in the presence and absence of cysteamine. NO production, iNOS induction, and iNOS signal were analyzed. Results.- IL-1 beta stimulated the inhibitory protein kappa B (I kappa B)/nuclear factor kappa B (NF kappa B) pathway, resulting in the activation of NF kappa B (nuclear translocation and DNA binding), which was followed by the induction of iNOS and NO production. The addition of IL-1 beta and cysteamine (1-4 mmol/L) markedly inhibited NO production, with a maximal effect at 4 mmol/L (80%-90% inhibition). Cysteamine also decreased the levels of iNOS protein and mRNA. Transfection experiments revealed that cysteamine decreased the transactivation activity of the iNOS promoter. An electrophoretic mobility shift assay demonstrated that cysteamine inhibited the activation of NF kappa B. Furthermore, cysteamine decreased the mRNA levels of the NF kappa B subunit p65 but increased those of the inhibitory protein I kappa B. Conclusions: These findings suggest that cysteamine inhibits iNOS induction at the step of NF kappa B activation. Further study is necessary to define the molecular basis of this effect of cysteamine on the regulation of NF kappa B and its pharmacologic implications.
