Induction of inducible nitric oxide synthase and proinflammatory cytokines expression by o,p'-DDT in macrophages.
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-1beta, IL-6, TNF-alpha) 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-kappaB sites were identified in the promoter of the iNOS and proinflammatory cytokines genes. Pretreating the cells with NF-kappaB 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-kappaB binding sites revealed that the o,p'-DDT-induced increase in the iNOS and proinflammatory cytokines expression level were mediated by the NF-kappaB transcription factor. However, pretreating the cells with o,p'-DDT and the NF-kappaB pathway inhibitors suppressed DDT-induced NF-kappaB 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-kappaB 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.
Kim
Ji Young
JY
Department Pharmacy, College of Pharmacy, Research Center for Proteineous Materials, Chosun University, 375 Seosuk-dong, Kwangju 501-759, South Korea.
Choi
Chul Yung
CY
Lee
Kyung Jin
KJ
Shin
Dong Weon
DW
Jung
Kyung Sik
KS
Chung
Young Chul
YC
Lee
Sang Seop
SS
Shin
Jae-Gook
JG
Jeong
Hye Gwang
HG
D000818:Animals; D002460:Cell Line; D003634:DDT / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004968:Estrogens, Non-Steroidal / Q000633:toxicity*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D015846:Monokines / Q000096:biosynthesis* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013047:Specific Pathogen-Free Organisms
D004968:Estrogens, Non-Steroidal; D015846:Monokines; D016328:NF-kappa B; D012333:RNA, Messenger; D009569:Nitric Oxide; D003634:DDT; C016340:o,p'-DDT; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse