2,2′,4,4′-Tetrachlorobiphenyl upregulates cyclooxygenase-2 in HL-60 cells via p38 mitogen-activated protein kinase and NF-κB

Abstract

Polychlorinated biphenyls (PCBs) are ubiquitous, persistent environmental contaminants that affect a number of cellular systems, including neutrophils. Among the effects caused by the noncoplanar PCB 2,2′,4,4′,-tetrachlorobiphenyl (2244-TCB) in granulocytic HL-60 cells are increases in superoxide anion production, activation of phospholipase A 2 with subsequent release of arachidonic acid (AA), and upregulation of the inflammatory gene cyclooxygenase-2 (COX-2). The objective of this study was to determine the signal transduction pathways involved in the upregulation of COX-2 by 2244-TCB. Treatment of HL-60 cells with 2244-TCB led to increased expression of COX-2 mRNA. This increase was prevented by the transcriptional inhibitor actinomycin D in cells pretreated with 2244-TCB for 10 minutes. The increase in COX-2 mRNA was associated with release of 3 H-AA, phosphorylation of p38 and extracellular signal-regulated kinase (ERK) mitogen-activated protein (MAP) kinases, increased levels of nuclear NF-κB and increased superoxide anion production. Bromoenol lactone, an inhibitor of the calcium-independent phospholipase A 2 , reduced 3 H-AA release but had no effect on COX-2 mRNA, protein or activity. Pretreatment with SB-202190 or SB-203580, inhibitors of the p38 MAP kinase pathway, prevented the 2244-TCBmediated induction of COX-2 and phosphorylation of p38 and ERK MAP kinases. These inhibitors did not alter 3 H-AA release. Treatment with PD 98059 or U 0126, inhibitors of the MAP/ERK (MEK) pathway, prevented the 2244-TCB-mediated activation of ERK but had no effect on COX-2 induction or p38 phosphorylation. 2244-TCB treatment did not affect c-Jun N-terminal kinase (JNK) phosphorylation. 2244-TCB exposure increased the amount of nuclear NF-κB. This increase was prevented by pretreatment with p38 MAP kinase inhibitors, but not by pretreatment with MEK inhibitors. Pretreatment with inhibitors of NF-κB prevented the 2244-TCB-mediated induction of COX-2 mRNA. 2244-TCB-mediated increases in superoxide anion were prevented by the NADPH oxidase inhibitor apocynin or the free radical scavenger 4-hydroxy TEMPO, but neither of these inhibitors affected the 2244-TCB-induced changes in COX-2 mRNA levels or 3 H-AA release. Taken together these data suggest that p38 MAP kinase-dependent activation of NF-κB is critical for the 2244-TCB-mediated upregulation of COX-2 mRNA.

NADPH oxidase and lipid raft-associated redox signaling are required for PCB153-induced upregulation of cell adhesion molecules in human brain endothelial cells

“…To support this notion, our results also indicate an increased superoxide production in PCB153-exposed hCMEC/D3 cells. These observations are supported by recent reports that selected ortho -PCBs, 2,2’-dichlorobiphenyl (PCB4) and 2,2’,4,4’-tetrachlorobiphenyl (PCB47) can induce ROS production in neutrophil granulocytes through Ca 2+ -dependent activation of NADPH oxidase (Bezdecny et al , 2007; Myhre et al , 2009). Novel data in the current study indicate that blockage of NADPH oxidase activation significantly attenuate PCB153-mediated upregulation of CAM proteins (Figure 5).…”

DDE and PCB 153 independently induce aryl hydrocarbon receptor (AhR) expression in peripheral blood mononuclear cells

“…In this respect, in a recent study, Alegría-Torres et al (Frigo et al, 2004;Kim et al, 2004). Similar findings were found for PCBs (Bezdecny et al, 2007;Glauert et al, 2008;Myhre et al, 2009;Wang et al, 2008). In line with the mechanism proposed by Champion et al (2013), our data showed that the over-expression of AhR was dependent on the TNF induced by DDE and PCB 153.…”

“…Those findings indicated that AhR expression in FLSs was stimulated in the presence of TNF, similar to our results here. Taking into account that data and our own, we hypothesize that TNF induced by DDE and PCB 153 (Alegría-Torres et al 2009; Cárdenas-González et al, 2013), likely via an NF-B pathway (Bezdecny et al, 2007;Frigo et al, 2004;Glauert et al, 2008;Kim et al, 2004;Myhre et al, 2009;Wang et al, 2008), was able to induce AhR mRNA expression.…”

Transcriptome Analysis in Peripheral Blood of Humans Exposed to Environmental Carcinogens: A Promising New Biomarker in Environmental Health Studies

“…MAPK14 gene expression returned correlations with most of the environmental carcinogens; PCBs, HCB, p,p ′-DDE, and Cd in blood as well as in urine. Upon environmental carcinogenic exposure, reported for PCB-47, MAPK14 functions as a mediator of COX2 gene expression ( Bezdecny et al 2007 ). In turn, COX2 expression is known to be deregulated in certain tumors.…”