Induction of inducible nitric oxide synthase and proinflammatory cytokines expression by o,p′-DDT in macrophages

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• 作者：Kim ; Ji Young ; Choi ; Chul Yung ; Lee ; Kyung Jin ; Shin ; Dong Weon ; Jung ; Kyung Sik ; Chung ; Young Chul ; et. al.
• 关键词：o ; p&prime ; -DDT ; Macrophages ; iNOS ; Inflammatory cytokines ; NF-κ ; B
• 刊名：Toxicology Letters
• 出版年：2004
• 期刊代码：49_03784274
• 类别：pha
• 出版时间：March 7, 2004
• 卷：147
• 期：3
• 页码：261-269
• 文件大小：197 K

摘要

Macrophages are crucial for the inflammatory response process because they release a number of proinflammatory mediators. 1,1,1-Trichloro-2-(p-chlorophenyl)-2-(o-chlorophenyl)ethane (o,p′-DDT) has been reported to possess immunomodulatory properties activity. However, its influence on cytokine production or the functions of the macrophages remains unclear. This study investigated the effects of o,p′-DDT on the production of nitric oxide (NO) and proinflammatory cytokines (IL-1β, IL-6, TNF-α) and analyzed the molecular mechanism in mouse macrophages. The addition of o,p′-DDT to macrophages induced NO and proinflammatory cytokines production in a dose-dependent manner. o,p′-DDT also increased inducible nitric oxide synthase (iNOS) and proinflammatory cytokines expression levels in the cells. NF-κB sites were identified in the promoter of the iNOS and proinflammatory cytokines genes. Pretreating the cells with NF-κB pathway inhibitors suppressed the iNOS and proinflammatory cytokines expression induced by o,p′-DDT. The transient expression and electrophoretic mobility shift assays with the NF-κB binding sites revealed that the o,p′-DDT-induced increase in the iNOS and proinflammatory cytokines expression level were mediated by the NF-κB transcription factor. However, pretreating the cells with o,p′-DDT and the NF-κB pathway inhibitors suppressed DDT-induced NF-κB activation. These results demonstrate that o,p′-DDT stimulates the production of NO and proinflammatory cytokines and can up-regulate the gene expression levels via NF-κB transactivation. Overall, the results of this study suggest evidence that o,p′-DDT might possess an inflammatory potential that is previously unrecognized immunomodulating activity of o,p′-DDT.