Methoxychlor-induced inducible nitric oxide synthase and proinflammatory cytokines expression in macrophages via NF-kappaB, ERK, and p38 mitogen-activated protein kinases.

ABSTRACT

Methoxychlor (MXC) is a pesticide that was developed as a replacement for dichlorodiphenyltrichloroethane. The influence of MXC on cytokine production or the functions of macrophages is unclear. This study examined the effects of MXC on the production of nitric oxide (NO) and the proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), and analyzed the molecular mechanism in mouse macrophages. The addition of MXC to macrophages induced the production of NO and proinflammatory cytokines and expression levels of these genes in a dose-dependent manner. The NF-kappaB sites were identified in the promoter of the iNOS and proinflammatory cytokines genes. The transient expression and electrophoretic mobility shift assays revealed that the NF-kappaB transcription factor mediated the MXC-induced increase in the iNOS and proinflammatory cytokines expression levels. In addition, MXC induced the rapid phosphorylation of the ERK1/2 and p38 MAPK. This demonstrates that MXC stimulates the production of NO and proinflammatory cytokines and can up-regulate the expression levels of these genes via NF-kappaB transactivation and ERK1/2 and p38 MAPK phosphorylation. Overall, this study provides evidence showing that MXC has inflammatory potential that is previously unrecognized immunomodulating activity.