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 hepati tis: the administration of Con A or of Pseudomonas aeroginosa exotoxin A (P EA). In both models, leptin-deficient (ob/ob) mice were protected from live r damage and showed lower induction of tumor necrosis factor (TNF) alpha an d IL-18 compared with their lean littermates. Neutralization of TNF-alpha r educed induction of IL-18 by either Con A (70% reduction) or PEA (40% reduc tion). 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 protec ted the mice against liver toxicity. However, neutralization of either IL-1 8 or TNF-alpha did not inhibit Con A-induced production of IFN-gamma. Thymu s atrophy and alterations in the number of circulating lymphocytes and mono cytes were observed in ob/ob mice. Exogenous leptin replacement restored th e responsiveness of ob/ob mice to Con A and normalized their lymphocyte and monocyte populations. These results demonstrate that leptin deficiency lea ds to reduced production of TNF-alpha and IL-18 associated with reduced T c ell-mediated hepatotoxicity. In addition, both TNF-alpha and IL-18 appear t o be essential mediators of T cell-mediated liver injury.