Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity:: Role of tumor necrosis factor α and IL-18
Leptin-deficient (ob/ob) mice are protected from T cell-mediated hepatotoxicity:: Role of tumor necrosis factor α and IL-18
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DOI：
10.1073/pnas.040561297
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发表时间：
2000-02-29
影响因子：
11.1
通讯作者：
Fantuzzi, G
中科院分区：
文献类型：
--
作者：
Faggioni, R;Jones-Carson, J;Fantuzzi, G
研究了瘦素在两种T细胞介导性肝炎模型中的作用：ConA和PEA。在这两个模型中，瘦素缺陷(ob/ob)小鼠受到保护，免受肝损伤，与其瘦小的后代相比，肿瘤坏死因子(TNF)α和IL-18的诱导较低。中和肿瘤坏死因子-α可减少ConA(减少70%)或PEA(减少40%)对IL-18的诱导。用可溶性肿瘤坏死因子受体或抗IL-18抗血清预处理瘦小鼠，可显著减少ConA和PEA引起的肝损伤。同时中和肿瘤坏死因子-α和白介素18，可完全保护小鼠免受肝脏毒性。然而，IL-18或TNF-α的中和并不能抑制ConA诱导的干扰素-γ的产生。Ob/ob小鼠胸腺萎缩，外周血淋巴细胞和单核细胞数量发生改变。外源性瘦素替代恢复了ob/ob小鼠对conA的反应性，并使其淋巴细胞和单核细胞数量正常化。这些结果表明，瘦素缺乏导致肿瘤坏死因子-α和IL-18的产生减少，这与T细胞介导的肝毒性降低有关。此外，肿瘤坏死因子-α和白介素18似乎都是T细胞介导的肝损伤的重要介质。
The role of leptin was investigated in two models of T cell-mediated hepatitis: the administration of Con A or of Pseudomonas aeroginosa 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.