title: Differential modification of inflammatory enzymes in J774A.1 macrophages by ochratoxin A alone or in combination with lipopolysaccharide.
abstract: Ochratoxin A (OTA) is a fungal metabolite with controversial immunomodulatory effects. A prolonged in vivo exposure to the mycotoxin may result in impaired immunity and decreased resistance to infections. In the present study, OTA modulation of lipopolysaccharide (LPS)-induced inflammatory process is described in the macrophagic cell line, J774A.1 in order to better understand the mechanisms underlying OTA immunotoxicity. OTA (30 nM-100 microM) induces a time and concentration dependent cytotoxic effect, increased when cells were co-stimulated with LPS (100 ng/ml), a concentration that alone did not modify the cellular viability. Moreover, OTA (3 microM) alone induces a significant increase in cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, while at the highest concentration (10 microM) a reduced expression of both enzymes was shown, consistently with the mycotoxin cytotoxic profile. The role of nuclear factor-kB (NF-kB) in the mycotoxin effect was also demonstrated. Conversely, when cells were co-stimulated with LPS, OTA showed a concentration-dependent reduction of COX-2 and iNOS expression and their respective metabolites (PGE(2) and NO). These results confirm the pro-inflammatory role of OTA by itself, and demonstrate the impaired capability of OTA-treated macrophages to respond properly to noxious stimuli, such as LPS, mimicking the environmental co-exposure to both compounds.
authors.affiliation: Department of Pathology and Animal Health, University of Naples Federico II, Via Delpino 1, 80137 Naples, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Ferrante
authors.forename: G Mattace
authors.initials: GM
authors.lastname: Raso
authors.forename: M
authors.initials: M
authors.lastname: Bilancione
authors.forename: E
authors.initials: E
authors.lastname: Esposito
authors.forename: A
authors.initials: A
authors.lastname: Iacono
authors.forename: R
authors.initials: R
authors.lastname: Meli
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015232:Dinoprostone / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051550:I-kappa B Kinase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008807:Mice, Inbred BALB C; D009569:Nitric Oxide / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D009793:Ochratoxins / Q000633:toxicity*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D009793:Ochratoxins; D051996:Transcription Factor RelA; C025589:ochratoxin A; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; D015232:Dinoprostone