title: Augmented fumonisin B1 toxicity in co-cultures: evidence for crosstalk between macrophages and non-parenchymatous liver epithelial cells involving proinflammatory cytokines.
abstract: Fumonisin B1, a common mycotoxin produced by Fusarium verticillioides found in corn, causes several fatal animal diseases. Liver and kidney are target organs of fumonisin B1 in laboratory animals, but primary rodent hepatocytes and liver slices were resistant to fumonisin B1-induced cytotoxic effects. We have shown that fumonisin B1 induces expression of tumor necrosis factor (TNF)alpha, interferon (IFN)gamma, and interleukine (IL) 12, in mouse liver. In various models of acute liver injury, a positive amplification loop involving TNFalpha, IFNgamma, and IL-12 has been implied that involves Kupffer cells (macrophages), hepatic lymphocytes and non-parenchymatous liver epithelial cells (NPECs). In the current study, cellular interactions in fumonisin B1-induced toxicity were investigated, using co-cultures of murine macrophages (J774A.1) and NPECs (NMuLi). Treatment of the co-cultures with fumonisin B1-produced cytotoxicity, whereas either J774A.1 or NMuLi cultures alone showed no response to the mycotoxin. Accumulation of sphinganine occurred to the similar extent in individual cultures as well as co-cultures. Expression of TNFalpha and IL-12 was increased in co-cultures but not in individual cultures. Transfer of conditioned medium from fumonisin B1-treated J774A.1 cells to NMuLi cultures produced an increase in IFNgamma expression in NMuLi cells. Results indicated that macrophages and liver epithelial cells interact in response to fumonisin B1 and potentiate the cytokines expression, which may have implications in making hepatocytes responsive to cytotoxicity of fumonisin B1.
authors.affiliation: Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens 30602-7389, USA.
authors.forename: Neelesh
authors.initials: N
authors.lastname: Sharma
authors.forename: Quanren
authors.initials: Q
authors.lastname: He
authors.forename: Raghubir P
authors.initials: RP
authors.lastname: Sharma
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002274:Carcinogens, Environmental / Q000633:toxicity*; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D018920:Coculture Techniques; D003470:Culture Media; D016207:Cytokines / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D037341:Fumonisins / Q000633:toxicity*; D007150:Immunohistochemistry; D007249:Inflammation / Q000503:physiopathology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D020239:Receptor Cross-Talk / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D002274:Carcinogens, Environmental; D003470:Culture Media; D016207:Cytokines; D037341:Fumonisins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C056933:fumonisin B1; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase