Fat diet and alcohol-induced steatohepatitis after LPS challenge in mice: role of bioactive TNF and Th1 type cytokines.
Obesity with insulin resistance and alcohol are the most frequent causes of steatohepatitis. This work investigates the contribution of bioactive TNF and Th1 type cytokines in a mouse model of steatohepatitis induced by FAT alone or FAT+EtOH and endotoxin. The extent of liver injury and cytokine activation induced by endotoxin in chronic FAT-fed mice, FAT+EtOH-fed mice, or mice fed standard chow were analyzed. Endotoxin administration to either FAT-fed or FAT+EtOH-fed mice increased serum ALT and AST compared to standard chow mice. Immunoreactive TNF was strongly activated by LPS in FAT-fed and FAT+EtOH-fed mice which presented the highest levels, but low levels were found in standard chow mice. In contrast, bioactive TNF was only present in serum of FAT-fed and in particular the highest levels were found in FAT+EtOH-fed mice. Moreover, soluble TNFR2 but not TNFR1 was found in lower amounts in serum of FAT+EtOH-fed mice compared to FAT-fed mice. Steatohepatitis was associated with increased IL-6, IFN-gamma, and iNOS mRNA and proteins. Data show that a moderately FAT diet and low-dose EtOH concur to generate steatohepatitis and TNF liver expression after LPS. In this model, changes in the regulation of TNF are associated with increased expression of IL-6, IFN-gamma, and iNOS.
Olleros
Maria L
ML
Department of Pathology and Immunology, Centre Médical Universitaire, 1 rue Michel-Servet, CH 1211 Geneva 4, Switzerland.
Martin
Maria L
ML
Vesin
Dominique
D
Fotio
Agathe L
AL
Santiago-Raber
Marie-Laure
ML
Rubbia-Brandt
Laura
L
Spahr
Laurent
L
Hadengue
Antoine
A
Garcia
Irene
I
D000818:Animals; D016207:Cytokines / Q000502:physiology*; D004041:Dietary Fats / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D000431:Ethanol / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D005235:Fatty Liver, Alcoholic / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D007371:Interferon-gamma / Q000502:physiology; D053762:Interleukin-12 Subunit p40 / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D008070:Lipopolysaccharides; D008099:Liver / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016207:Cytokines; D004041:Dietary Fats; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D007371:Interferon-gamma; D009195:Peroxidase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse