title: Regulation of IL-8 promoter activity by verrucarin A in human monocytic THP-1 cells.
abstract: Macrocyclic trichothecenes have been frequently detected in fungi in water-damaged buildings and exhibited higher toxicity than the well-studied trichothecenes; however, the mechanism underlying their toxicity has been poorly understood. In this study, transcriptional regulation of the cytokine interleukin (IL)-8 by a macrocyclic trichothecene, verrucarin A (VA), in human monocytic THP-1 cells is reported. Consistent with previous findings, VA was 100-fold more cytotoxic than deoxynivalenol (DON), while ochratoxin A (OA) was not cytotoxic. In cells transduced with the wild-type IL-8 promoter luciferase construct, VA induced a biphasic dose response composed of an upregulation of luciferase expression at low concentrations of 0.01-1 ng/ml and a downregulation at high levels of 10 ng/ml and higher. In contrast, DON induced a sigmoid-shaped dose response with the EC50 of 11.6 ng/ml, while OA did not markedly affect the IL-8 expression. When cells were transduced with IL-8 promoter with a mutation of transcription factor nuclear factor-κB (NF-κB)-binding site, VA (1 ng/ml), DON (1000 ng/ml), and tumor necrosis factor (TNF) α (20 ng/ml)-induced luciferase expression were impaired. In addition, the NF-κB inhibitor caffeic acid phenethyl ester inhibited VA-, DON-, and TNFα-induced luciferase expression. Mutation of the CCAAT/enhancer-binding protein (CEBP) β binding site of the IL-8 promoter affected only DON-, but not VA- and TNFα-induced luciferase expression. Taken together, these results suggested that VA activated IL-8 promoter via an NF-κB-dependent, but not CEBPβ-dependent, pathway in human monocytes.
authors.affiliation: a Department of Civil and Environmental Engineering , University of Texas at San Antonio , San Antonio , Texas , USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Steve O
authors.initials: SO
authors.lastname: Simmons
authors.forename: Ruoting
authors.initials: R
authors.lastname: Pei
mesh_terms: D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009793:Ochratoxins / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014255:Trichothecenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D016209:Interleukin-8; D016328:NF-kappa B; D009793:Ochratoxins; D014255:Trichothecenes; D014409:Tumor Necrosis Factor-alpha; C025589:ochratoxin A; D008156:Luciferases; C007262:deoxynivalenol; C005348:muconomycin A