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.
References
[1]
Joint FAO/WHO. Ochratoxin A. In Safety evaluation of certain mycotoxins in food. Prepared by the 56th Meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). WHO Food Additives Series L: 46; International Programme on Food Safety. World Health Organization: Geneva, Switzerland, 2001; pp. 281–415.
[2]
EFSA. Opinion of the scientific panel on contaminations in the food chain on a request from the commission related to ochratoxin A in food. EFSA J.？2006, 365, 1–56.
[3]
Ringot, D.; Chango, A.; Schneider, Y.J.; Larondelle, Y. Toxicokinetics and toxicodynamics of ochratoxin A, an update. Chem. Biol. Interact.？2006, 159, 18–46.
[4]
Pfohl-Leszkowicz, A.; Manderville, R.A. Ochratoxin A: An overview on toxicity and carcinogenicity in animals and humans. Mol. Nutr. Food Res.？2007, 51, 61–99.
[5]
Al-Anati, L.; Petzinger, E. Immunotoxic activity of ochratoxin A. J. Vet. Pharmacol. Therap.？2006, 29, 79–90.
[6]
álvarez, L.; Gil, A.G.; Ezpeleta, O.; Garcia-Jalon, J.A.; Lopez de Cerain, A. Immunotoxic effects of ochratoxin A in wistar rats after oral administration. Food Chem. Toxicol.？2004, 42, 825–834.
[7]
Al-Anati, L.; Katz, N.; Petzinger, E. Interference of arachidonic acid and its metabolites with TNF-α release by ochratoxin A from rat liver. Toxicology？2005, 208, 335–346.
[8]
Weidenbach, A.; Schuh, K.; Failing, K.; Petzinger, E. Ochratoxin A induced TNF-α release from the isolated and blood-free perfused rat liver. Mycotoxin Res.？2000, 16A, 189–193.
[9]
Al-Anati, L.; Reinehr, R.; Van Rooijen, N.; Petzinger, E. In vitro Induction of Tumor Necrosis Factor-α by Ochratoxin A from Rat Liver: Role of Kupffer cells. Mycotoxin Res.？2005, 21, 172–175.
[10]
Petzinger, E.; Weidenbach, A. Mycotoxins in the food chain: The role of ochratoxins. Livestock Prod. Sci.？2002, 76, 245–250.
[11]
Kopp, E.; Medzhitov, R. The Toll-receptor family and control of innate immunity. Curr. Opin. Immunol.？1999, 11, 13–18.
[12]
Kopp, E.; Medzhitov, R. Recognition of microbial infection by Toll-like receptors. Curr. Opin. Immunol.？2003, 15, 396–401.
[13]
Al-Anati, L.; Essid, E.; Reinehr, R.; Petzinger, E. Silibinin protects OTA-mediated TNF-alpha release from perfused rat livers and isolated rat Kupffer cells. Mol. Nutr. Food Res.？2009, 53, 460–466, doi:10.1002/mnfr.200800110. 19156713
He, Q.; Kim, J.; Sharma, R.P. Fumonisin B1 hepatotoxicity in mice is attenuated by depletion of Kupffer cells by gadolinium chloride. Toxicology？2005, 207, 137–147.
[16]
Cusumano, V.; Costa, G.B.; Trifiletti, R.; Merendino, R.A.; Mancuso, G. Functional impairment of rat Kupffer cells induced by aflatoxin B1 and its metabolites. FEMS Immunol. Med. Microbiol.？1995, 10, 151–155.
[17]
Arii, S.; Imamura, M. Physiological role of sinusoidal endothelial cells and Kupffer cells and their implication in the pathogenesis of liver injury. J. Hepatobiliary Pancreat Surg.？2000, 7, 40–48.
[18]
Neyrinck, A. Modulation of Kupffer cell activity: physio-pathological consequences on hepatic metabolism. Bull. Mem. Acad. R. Med. Belg.？2004, 159, 358–366.
[19]
Neyrinck, A.M.; Margagliotti, S.; Gomez, C.; Delzenne, N.M. Kupffer cell-derived prostaglandin E2 is involved in regulation of lipid synthesis in rat liver tissue. Cell Biochem. Funct.？2004, 22, 327–332.
[20]
Peters, T.; Karck, U.; Decker, K. Interdependence of tumor necrosis factor, prostaglandin E2, and protein synthesis in lipopolysaccharide-exposed rat Kupffer cells. Eur. J. Biochem.？1990, 191, 583–589, doi:10.1111/j.1432-1033.1990.tb19161.x. 2390987
[21]
Lazar, G., Jr.; Lazar, G.; Olah, J.; Husztik, E.; Duda, E. Effect of kupffer cell phagocytosis blockade indyced by gadolinium chloride and carrageenan on endotoxin sensitivity. Tissue localization of endotoxin and TNF production. J. Alloys Comp.？1995, 225, 623–625, doi:10.1016/0925-8388(94)07074-1.
[22]
Diehl, A.M. Cytokine regulation of liver regeneration. In Normal and Malignant Liver Cell Growth; Fleig, W.E., Ed.; Kluwer Academic Publisher: Lancaster, UK, 1999; pp. 47–55.
[23]
Higuchi, H.; Kurose, I.; Watanabe, N.; Takaishi, M.; Ebinuma, H.; Saito, H.; Miura, S.; Ishii, H. Nitric oxide and tumor necrosis factor-α released from Kupffer cells synergistically mediate apoptosis of hepatoma cells: involvement of CD18/ ICAM-1-dependent NFkB activation process. In Cells of Hepatic Sinusoid; Knook, D.L., Wisse, E., Balabaud, C., Eds.; Kupffer Cell Foundation: Leiden, The Netherland, 1997; Volume 6, pp. 326–329.
[24]
Pagliara, P.; Carla, E.C.; Caforio, S.; Chionna, A.; Massa, S.; Abbro, L.; Dini, L. Kupffer cells promote lead nitrate-induced hepatocyte apoptosis via oxidative stress. Comp. Hepatol.？2003, 2, 8, doi:10.1186/1476-5926-2-8. 12921539
[25]
Atroshi, F.; Biese, I.; Saloniemi, H.; Ali-Vehmas, T.; Saari, S.; Rizzo, A.; Veijalainen, P. Significance of apoptosis and its relationship to antioxidants after ochratoxin A administration in mice. J. Pharm. Pharm. Sci.？2000, 3, 281–291.
[26]
Chopra, M.; Link, P.; Michels, C.; Schrenk, D. Characterization of ochratoxin A-induced apoptosis in primary rat hepatocytes. Cell Biol. Toxicol.？2009.
[27]
Heller, M.; Rosner, H.; Burkert, B.; Moller, U.; Hinsching, A.; Rohrmann, B.; Thierbach, S.; Kohler, H. In vitro studies into the influence of ochratoxin A on the production of tumor necrosis factor alpha by the human monocytic cell line THP-1. Dtsch Tierarztl Wochenschr.？2002, 109, 200–205. 11998373
[28]
Wang, H.C.; Zhang, H.; Zhou, T.L. Protective effect of hydrophilic Salvia monomer on liver ischemia/reperfusion injury induced by pro-inflammatory cytokines. Zhongguo Zhong Xi Yi Jie He Za Zhi？2002, 22, 207–210.
[29]
Sakurai, F.; Terada, T.; Yasuda, K.; Yamashita, F.; Takakura, Y.; Hashida, M. The role of tissue macrophages in the induction of proinflammatory cytokine production following intravenous injection of lipoplexes. Gene Ther.？2002, 9, 1120–1126.
[30]
Hayakawa, M.; Ishida, N.; Takeuchi, K.; Shibamoto, S.; Hori, T.; Oku, N.; Ito, F.; Tsujimoto, M. Arachidonic acid-selective cytosolic phospholipase A2 is crucial in the cytotoxic action of tumor necrosis factor. J. Biol. Chem.？1993, 268, 11290–11295.
[31]
Hayakawa, M.; Oku, N.; Takagi, T.; Hori, T.; Shibamoto, S.; Yamanaka, Y.; Takeuchi, K.; Tsujimoto, M.; Ito, F. Involvement of prostaglandin-producing pathway in the cytotoxic action of tumor necrosis factor. Cell Struct. Funct.？1991, 16, 333–340.
[32]
Ferrante, M.C.; Raso, G.M.; Bilancione, M.; Esposito, E.; Iacono, A.; Meli, R. Differential modification of inflammatory enzymes in J774A.1 macrophages by ochratoxin A alone or in combination with lipopolysaccharide. Toxicol. Lett.？2008, 181, 40–46, doi:10.1016/j.toxlet.2008.06.866. 18647641
[33]
De Nardo, D.; De Nardo, C.M.; Nguyen, T.; Hamilton, J.A.; Scholz, G.M. Signaling crosstalk during sequential TLR4 and TLR9 activation amplifies the inflammatory response of mouse macrophages. J. Immunol.？2009, 183, 8110–8118.
[34]
Opal, S.M.; Huber, C.E. Bench-to-bedside review: Toll-like receptors and their role in septic shock. Crit. Care？2002, 6, 125–136.
[35]
Qureshi, S.T.; Lariviere, L.; Leveque, G.; Clermont, S.; Moore, K.J.; Gros, P.; Malo, D. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J. Exp. Med.？1999, 189, 615–625.
[36]
Roach, J.C.; Glusman, G.; Rowen, L.; Kaur, A.; Purcell, M.K.; Smith, K.D.; Hood, L.E.; Aderem, A. The evolution of vertebrate Toll-like receptors. Proc. Natl. Acad. Sci. USA？2005, 102, 9577–9582.
[37]
Vogel, S.N.; Perera, P.Y.; Detore, G.R.; Bhat, N.; Carboni, J.M.; Haziot, A.; Goyert, S.M. CD14 dependent and independent signaling pathways in murine macrophages from normal or CD 14 "knockout" (CD14 KO) mice stimulated with LPS or taxol. Prog.Clin. Biol. Res.？1998, 397, 137–146.
[38]
Lentschat, A.; Karahashi, H.; Michelsen, K.S.; Thomas, L.S.; Zhang, W.; Vogel, S.N.; Arditi, M. Mastoparan, a G protein agonist peptide, differentially modulates TLR4- and TLR2-mediated signaling in human endothelial cells and murine macrophages. J. Immunol.？2005, 174, 4252–4261.
O'Neill, L.A.; Bowie, A.G. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat. Rev. Immunol.？2007, 7, 353–364.
[41]
Sauvant, C.; Holzinger, H.; Gekle, M. The nephrotoxin ochratoxin A induces key parameters of chronic interstitial nephropathy in renal proximal tubular cells. Cell Physiol. Biochem.？2005, 15, 125–134.
[42]
Sauvant, C.; Holzinger, H.; Gekle, M. Proximal tubular toxicity of ochratoxin A is amplified by simultaneous inhibition of the extracellular signal-regulated kinases 1/2. J. Pharmacol. Exp. Ther.？2005, 313, 234–241.
[43]
Kirkland, T.N.; Finley, F.; Leturcq, D.; Moriarty, A.; Lee, J.D.; Ulevitch, R.J.; Tobias, P.S. Analysis of lipopolysaccharide binding by CD14. J. Biol. Chem.？1993, 268, 24818–24823. 7693705
[44]
Hailman, E.; Lichenstein, H.S.; Wurfel, M.M.; Miller, D.S.; Johnson, D.A.; Kelly, M.; Busse, L.A.; Zukowski, M.M.; Wright, S.D. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J. Exp. Med.？1994, 179, 269–277.
[45]
Arditi, M.; Zhou, J.; Dorio, R.; Rong, G.W.; Goyert, S.M.; Kim, K.S. Endotoxin-mediated cell injury and activation: role of soluble CD14. Infect. Immun.？1993, 61, 3149–3156.
[46]
Arditi, M.; Zhou, J.; Torres, M.; Durden, D.L.; Stins, M.; Kim, K.S. Lipopolysaccharide stimulates the tyrosine phosphorylation of mitogen-activated protein kinases p44, p42, and p41 in vascular endothelial cells in a soluble CD14-dependent manner. J. Immunol.？1995, 155, 3994–4003.
[47]
Haziot, A.; Rong, G.W.; Silver, J.; Goyert, S.M. Recombinant soluble CD14 mediates the activation of endothelial cells by lipopolysaccharide. J. Immunol.？1993, 151, 1500–1507. 7687634
[48]
Eyhorn, S.; Schlayer, H.J.; Henninger, H.P.; Dieter, P.; Hermann, R.; Woort-Menker, M.; Becker, H.; Schaefer, H.E.; Decker, K. Rat hepatic siniusiodal endothelial cells in monolayer culture. Biochemical and ultrastructural characteristics. J. Hepatol.？1988, 6, 23–35, doi:10.1016/S0168-8278(88)80459-8. 3279104
[49]
Petzinger, E.; Müller, N.; F？llmann, W.; Deutscher, J.; Kinne, R.K. Uptake of bumetanide into isolated rat hepatocytes and primary liver cell cultures. Am. J. Physiol.？1989, 256, G78–G86.
[50]
Renz, H.; Gong, J.H.; Schmidt, A.; Nain, M.; Gemsa, D. Release of tumor necrosis factors-α from macrophages enhancement and suppression are dose-dependantly regulated by prostaglandin E2 and cyclic nucleotides. J. Immunol.？1988, 141, 2388–2393.
