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Differential Cell Sensitivity between OTA and LPS upon Releasing TNF-α
Institute of Pharmacology and Toxicology, College of Veterinary Medicine, Justus Liebig University Giessen. Frankfurter Street 107, D-35392 Giessen, Germany
Institute of Environmental Medicine, Karolinska Institutet, S-17177 Stockholm, Sweden
Rudolf-Buchheim-Institute of Pharmacology, College of Medicine, Justus Liebig University Giessen, Frankfurter Street 107, D-35392 Giessen, Germany
* Author to whom correspondence should be addressed.
Received: 6 May 2010; in revised form: 28 May 2010 / Accepted: 28 May 2010 / Published: 1 June 2010
(This article belongs to the Special Issue Ochratoxins
Abstract: The release of tumor necrosis factor α (TNF-α) by ochratoxin A (OTA) was studied in various macrophage and non-macrophage cell lines and compared with E. coli lipopolysaccharide (LPS) as a standard TNF-α release agent. Cells were exposed either to 0, 2.5 or 12.5 µmol/L OTA, or to 0.1 µg/mL LPS, for up to 24 h. OTA at 2.5 µmol/L and LPS at 0.1 µg/mL were not toxic to the tested cells as indicated by viability markers. TNF-a was detected in the incubated cell medium of rat Kupffer cells, peritoneal rat macrophages, and the mouse monocyte macrophage cell line J774A.1: TNF-a concentrations were 1,000 pg/mL, 1,560 pg/mL, and 650 pg/mL, respectively, for 2.5 µmol/L OTA exposure and 3,000 pg/mL, 2,600 pg/mL, and 2,115 pg/mL, respectively, for LPS exposure. Rat liver sinusoidal endothelial cells, rat hepatocytes, human HepG2 cells, and mouse L929 cells lacked any cytokine response to OTA, but showed a significant release of TNF-a after LPS exposure, with the exception of HepG2 cells. In non-responsive cell lines, OTA lacked both any activation of NF-κB or the translocation of activated NF-κB to the cell nucleus, i.e., in mouse L929 cells. In J774A.1 cells, OTA mediated TNF-a release via the pRaf/MEK 1/2–NF-κB and p38-NF-κB pathways, whereas LPS used pRaf/MEK 1/2-NF-κB, but not p38-NF-κB pathways. In contrast, in L929 cells, LPS used other pathways to activate NF-κB. Our data indicate that only macrophages and macrophage derived cells respond to OTA and are considered as sources for TNF-a release upon OTA exposure.
Keywords: ochratoxin A; lipopolysaccharide; tumor necrosis factor α; Kupffer cells; macrophages; rat liver sinusoidal endothelial cells; HepG2 cells; rat hepatocytes
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Al-Anati, L.; Essid, E.; Stenius, U.; Beuerlein, K.; Schuh, K.; Petzinger, E. Differential Cell Sensitivity between OTA and LPS upon Releasing TNF-α. Toxins 2010, 2, 1279-1299.
Al-Anati L, Essid E, Stenius U, Beuerlein K, Schuh K, Petzinger E. Differential Cell Sensitivity between OTA and LPS upon Releasing TNF-α. Toxins. 2010; 2(6):1279-1299.
Al-Anati, Lauy; Essid, Ebtisam; Stenius, Ulla; Beuerlein, Knut; Schuh, Klaus; Petzinger, Ernst. 2010. "Differential Cell Sensitivity between OTA and LPS upon Releasing TNF-α." Toxins 2, no. 6: 1279-1299.