Risk assessment of tetrabromobisphenol A on cyclooxygenase-2 expression via MAP kinase/NF-kappaB/AP-1 signaling pathways in murine macrophages.
Tetrabromobisphenol A [2,2-bis-(3,5-dibromo-4-hydroxyphenyl)propane; TBBPA] is used worldwide as a flame retardant in numerous products. In the present study, the effects of TBBPA were examined on the expression of cyclooxygenase-2 (COX-2), inflammation-related cytokines, transcription factors, and signaling pathways responsible for transcriptional activation of the COX-2 gene in murine RAW 264.7 macrophages. Exposure to TBBPA markedly enhanced the production of prostaglandin E(2), a major COX-2 metabolite, in macrophages. TBBPA concentration-dependently increased the levels of COX-2 protein and mRNA. In addition, TBBPA increased the secretion and mRNA levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta. Transfection of a human COX-2 promoter construct demonstrated that TBBPA induced COX-2 promoter activity. Furthermore, transfection with pNF-kappaB-Luc and pAP-1-Luc plasmid revealed that TBBPA activated the NF-kappaB and AP-1 sites. Phosphatidylinositol 3 (PI3) kinase, its downstream signaling molecule, Akt, and mitogen-activated protein kinases (MAPK) were also significantly activated by TBBPA. Our data demonstrate TBBPA-induced COX-2 and proinflammatory cytokine expression occurs through the PI3-kinase/Akt/MAP kinase/NF-kappaB/AP-1 pathways.
Han
Eun Hee
EH
College of Pharmacy, Chosun University, Gwangju, South Korea.
Park
Jin Hee
JH
Kang
Keon Wook
KW
Jeong
Tae Cheon
TC
Kim
Hyung Sik
HS
Jeong
Hye Gwang
HG
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005411:Flame Retardants / Q000008:administration & dosage / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D015394:Molecular Structure; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D000073718:Pancreatitis-Associated Proteins; D011075:Polybrominated Biphenyls / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*
D005411:Flame Retardants; D016328:NF-kappa B; D000073718:Pancreatitis-Associated Proteins; D011075:Polybrominated Biphenyls; C000612141:REG3A protein, human; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; D020929:Mitogen-Activated Protein Kinase Kinases; C020806:tetrabromobisphenol A; D015232:Dinoprostone