Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18 - PubMed (original) (raw)
Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity: role of tumor necrosis factor alpha and IL-18
R Faggioni et al. Proc Natl Acad Sci U S A. 2000.
Abstract
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.
Figures
Figure 1
Reduced liver damage in ob/ob compared with +/? mice after administration of Con A. +/? and ob/ob mice received an i.v. injection of Con A or saline. Blood was collected at various times thereafter for measurement of ALT levels. Data are mean ± SEM of five mice per group. ***, P < 0.001 vs. +/? mice by unpaired Student's t test. (Inset) +/? and ob/ob mice received an i.p. injection of LPS (0.5 mg/kg). Blood was collected 24 h later for measurement of ALT levels. Data are mean ± SEM of five mice per group. *, P < 0.05 vs. +/? mice by unpaired Student's t test.
Figure 2
Reduced TNF-α and IL-18 in ob/ob compared with +/? mice. +/? and ob/ob mice received an i.v. injection of Con A or saline. (A) Serum TNF-α levels at 1 h. (B) IL-18 levels at 6 h. Data are mean ± SEM of five mice per group. **, P < 0.01; ***, P < 0.001 vs. +/? mice by unpaired Student's t test.
Figure 3
Reduced PEA-induced hepatotoxicity and cytokine production in ob/ob mice. Ob/ob and +/? mice received an i.v. injection of either PEA or vehicle. Blood was collected at 16 h for measurement of serum ALT (A), TNF-α (B), or IL-18 (C) levels. Data are mean ± SEM of five mice per group. ***, P < 0.001 vs. +/? mice by unpaired Student's t test.
Figure 4
TNF-α neutralization inhibits induction of IL-18 by Con A. C57BL/6J mice received an i.p. injection of TNFsRp55 or saline, immediately followed by the i.v. administration of either Con A or saline. Blood was collected at 3, 6, or 18 h for evaluation of IL-18 levels. Data are mean ± SEM of five mice per group. ***, P < 0.001 vs. corresponding vehicle by unpaired Student's t test.
Figure 5
Blockade of TNF-α and IL-18 protects mice from Con A- and PEA-induced hepatotoxicity. C57BL/6J mice received an i.p. injection of either TNFsRp55, anti-IL-18 antiserum, a combination of TNFsRp55 and anti-IL-18 antiserum or vehicle, immediately followed by the i.v. administration of Con A (A) or PEA (B). Data are mean ± SEM of five mice per group. **, P < 0.01; ***, P < 0.001 vs. Con A or PEA alone; ‡‡, P < 0.01 vs. either TNFsRp55 or anti-IL-18 by factorial ANOVA.
Figure 6
Leptin replacement restores responsiveness to Con A in ob/ob mice. Ob/ob mice received two daily injections of either saline (ob/ob) or leptin (leptin-replaced ob/ob) for 10 days. +/? mice remained untreated. After treatment, mice received an i.v. injection of either saline or Con A. (A) Serum ALT at 24 h. (B) Serum TNF-α at 1 h. (C) Serum IL-18 at 6 h. Data are mean ± SEM of seven mice per group. **, P < 0.01; ***, P < 0.001 vs. ob/ob mice; ‡‡, P < 0.01 vs. leptin-replaced ob/ob mice by factorial ANOVA.
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