title: Fumonisin-induced tumor necrosis factor-alpha expression in a porcine kidney cell line is independent of sphingoid base accumulation induced by ceramide synthase inhibition.
abstract: Previous studies have shown that fumonisin B1 (FB1) inhibits ceramide synthase, resulting in accumulation of free sphinganine and sphingosine. Tumor necrosis factor-alpha (TNFalpha) plays an important role in FB1 toxicity and the expression of TNFalpha mRNA in liver and kidney is increased following FB1 exposure in mice. The objective of the current study was to investigate whether these two events (sphingoid bases accumulation and TNFalpha induction) are dependent on each other. An increase in expression of TNFalpha mRNA was detected in LLC-PK1 cells as early as 4 h after FB1 treatment but decreased to the control levels after 8 h. A positive linear correlation was observed between the expression of TNFalpha mRNA and FB1 concentration. Increases of intracellular sphingoid bases were also detected after 4 h of FB1 treatment and progressively increased until 24 h. Exposure of the cells to sphinganine or sphingosine did not significantly alter the expression of TNFalpha. Inhibition of sphingoid base biosynthesis by ISP-1, a specific inhibitor of serine palmitoyltransferase, the first enzyme in de novo sphingolipid biosynthesis, efficiently blocked the accumulation of free sphingoid bases in response to FB1, but it did not prevent the induction of TNFalpha expression. Results indicate that FB1-induced increase in TNFalpha expression is independent of sphingoid base accumulation-induced by ceramide synthase inhibition in LLC-PK1 cells.
authors: Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, Georgia 30602, USA.
authors: Q
authors: Q
authors: He
authors: R T
authors: RT
authors: Riley
authors: R P
authors: RP
authors: Sharma
mesh_terms: D000217:Acyltransferases / Q000037:antagonists & inhibitors; D000818:Animals; D002264:Carboxylic Acids / Q000494:pharmacology*; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D037341:Fumonisins; D015870:Gene Expression / Q000187:drug effects*; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009281:Naphthalenes / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051102:Serine C-Palmitoyltransferase; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D002264:Carboxylic Acids; D002518:Ceramides; D004791:Enzyme Inhibitors; D005229:Fatty Acids, Monounsaturated; D037341:Fumonisins; D009281:Naphthalenes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C101954:N-caproylsphingosine; C056933:fumonisin B1; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D000217:Acyltransferases; D051102:Serine C-Palmitoyltransferase; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; C058819:calphostin C; D013110:Sphingosine; C005682:safingol; C001996:thermozymocidin