Expression of Cyclooxygenase-2 and Pro-inflammatory Cytokines Induced by 2,2',4,4',5,5'-Hexachlorobiphenyl (PCB 153) in Human Mast Cells Requires NF-.KAPPA.B Activation.

Abstract

Mast cells are critical for initiating innate immune and inflammatory responses by releasing a number of pro-inflammatory mediators. The potential immunomodulatory properties of hydrogenated aromatic hydrocarbons have been the subject of extensive investigation, as the immune system is a sensitive target for hydrogenated aromatic hydrocarbon toxicity. In this report, the effects of polychlorinated biphenyl (PCB) on the expression of cyclooxygenase-2 and pro-inflammatory cytokines such as interleukin-1beta (IL-1beta), IL-6 and tumor necrosis factor (TNF)-alpha in the human leukemic mast cell line were investigated. TNF-alpha and IL-1beta expressed their respective mRNA in the presence or absence of PCB, while cyclooxygenase-2 (COX-2) and IL-6 mRNA expression were highly induced by PCB after 2 h. Moreover, pre-treatment with the nuclear factor (NF)-kappaB pathway inhibitor, pyrrolidine dithiocarbamate, suppressed COX-2, TNF-alpha and IL-1beta induction and reduced the IL-6 mRNA levels induced by PCB. The NF-kappaB activity was determined by electrophoretic mobility shift analysis (EMSA) using an oligonucleotide containing a consensus NF-kappaB binding sequence. Stimulating the cells with PCB activated NF-kappaB. However, pre-treating them with a NF-kappaB pathway inhibitor, pyrrolidine dithiocarbamate, suppressed PCB-induced NF-kappaB activation. This suggests that PCB induces cycloxoygenase-2 and pro-inflammatory cytokine expression, and that this induction occurs through NF-kappaB.