Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18.
The role of leptin was investigated in two models of T cell-mediated hepatitis: the administration of Con A or of Pseudomonas aeruginosa exotoxin A (PEA). In both models, leptin-deficient (ob/ob) mice were protected from liver damage and showed lower induction of tumor necrosis factor (TNF) alpha and IL-18 compared with their lean littermates. Neutralization of TNF-alpha reduced induction of IL-18 by either Con A (70% reduction) or PEA (40% reduction). Pretreatment of lean mice with either soluble TNF receptors or with an anti-IL-18 antiserum significantly reduced Con A- and PEA-induced liver damage. The simultaneous neutralization of TNF-alpha and IL-18 fully protected the mice against liver toxicity. However, neutralization of either IL-18 or TNF-alpha did not inhibit Con A-induced production of IFN-gamma. Thymus atrophy and alterations in the number of circulating lymphocytes and monocytes were observed in ob/ob mice. Exogenous leptin replacement restored the responsiveness of ob/ob mice to Con A and normalized their lymphocyte and monocyte populations. These results demonstrate that leptin deficiency leads to reduced production of TNF-alpha and IL-18 associated with reduced T cell-mediated hepatotoxicity. In addition, both TNF-alpha and IL-18 appear to be essential mediators of T cell-mediated liver injury.
Faggioni
R
R
Metabolism Section, Department of Veteran Affairs Medical Center, University of California, San Francisco, CA 94121, USA.
Jones-Carson
J
J
Reed
D A
DA
Dinarello
C A
CA
Feingold
K R
KR
Grunfeld
C
C
Fantuzzi
G
G
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism; D003208:Concanavalin A / Q000633:toxicity; D005098:Exotoxins / Q000633:toxicity; D005260:Female; D020382:Interleukin-18 / Q000276:immunology* / Q000378:metabolism; D020738:Leptin / Q000276:immunology* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D003208:Concanavalin A; D005098:Exotoxins; D020382:Interleukin-18; D020738:Leptin; D014409:Tumor Necrosis Factor-alpha; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A