Paradoxical role of tumor necrosis factor alpha in fumonisin-induced hepatotoxicity in mice.
Tumor necrosis factor alpha (TNFalpha) is involved in fumonisin-induced hepatotoxic effects in mice. The hepatic response to fumonisin B(1) (FB(1)) was reduced in transgenic animals lacking either of the two TNFalpha receptors. In the present study, we hypothesized that the effect of a similar fumonisin treatment in animals lacking either TNFalpha or both TNFalpha receptors would be considerably less than their wild type (WT) counterparts. The FB(1)-induced increase in circulating liver enzymes was enhanced by deletion of TNFalpha or unchanged in mice lacking both TNFalpha receptors. These findings corresponded with the degree of toxicity as established by microscopic examination of liver. FB(1) induced the expression of TNFalpha in the liver of all strains, except the animals with a deleted TNFalpha gene. The FB(1)-mediated increases in liver sphingosine or sphinganine paralleled the hepatotoxic responses. It is apparent that the presence of TNFalpha is not necessary for FB(1)-induced hepatotoxicity in mice and a lack of the function of this cytokine may aggravate the hepatotoxic responses to fumonisins, perhaps by preventing repair mechanisms or by expression of other signaling molecules. These observations were in accordance with our previous finding where over-expression of TNFalpha also protected against FB(1)-mediated hepatotoxicity, and with the reported beneficial functions of low-level TNFalpha in tissue regeneration.
Sharma
Raghubir P
RP
Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602, USA. rpsharma@vet.uga.edu
He
Quanren
Q
Meredith
Filmore I
FI
Riley
Ronald T
RT
Voss
Kenneth A
KA
D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D017931:DNA Primers; D004906:Erythrocyte Count; D037341:Fumonisins / Q000633:toxicity*; D007958:Leukocyte Count; D008099:Liver / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D009183:Mycotoxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D015398:Signal Transduction / Q000502:physiology; D013107:Sphingolipids / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000502:physiology*
D015703:Antigens, CD; D017931:DNA Primers; D037341:Fumonisins; D009183:Mycotoxins; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D013107:Sphingolipids; D014409:Tumor Necrosis Factor-alpha