Mengozzi M, Sironi M, Gadina M, Ghezzi P
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
J Immunol. 1991 Aug 1;147(3):899-902.
The development of LPS tolerance has been suggested to be mediated by an inhibition of cytokine synthesis. Here we have studied serum IL-6 and TNF levels in mice after LPS administration. Repeated administration of LPS (35 micrograms daily for 4 days) to mice induced a refractoriness (tolerance) to subsequent administrations of LPS in terms of induction of circulating IL-6 and TNF. To investigate the mechanism by which LPS down-regulates its own induction of cytokine synthesis and the relationship between IL-6 and TNF production, we attempted to revert the inhibition of IL-6 and TNF production using agents like PMA or IFN-gamma, previously reported to activate macrophage production of cytokines. Pretreatment with PMA (4 micrograms, 10 min before LPS) partially restored IL-6 production in LPS-tolerant mice given 2 micrograms LPS. On the other hand, PMA did not restore TNF induction in LPS-tolerant mice, even when administered with high doses of LPS (up to 200 micrograms). A similar reversal of LPS resistance to IL-6, but not TNF, induction by PMA was observed in genetically LPS-resistant C3H/HeJ mice. IFN-gamma also restored, although to a lesser extent than PMA, IL-6 production. However, unlike PMA, IFN-gamma could also partially restore TNF production in LPS-tolerant mice, although only when LPS was administered at high doses. By contrast with PMA, IFN-gamma was clearly more active in restoring TNF synthesis than that of IL-6. Similar results were obtained in genetically LPS-unresponsive C3H/HeJ mice. These data suggest that different mechanisms are implicated in the inhibition of IL-6 and TNF synthesis in LPS-tolerant mice and that part of this inhibition can be overcome by PMA or IFN-gamma.
有人提出，脂多糖耐受性的形成是由细胞因子合成的抑制介导的。在此，我们研究了脂多糖给药后小鼠血清白细胞介素-6（IL-6）和肿瘤坏死因子（TNF）水平。对小鼠重复给药脂多糖（每天35微克，共4天），就循环IL-6和TNF的诱导而言，会诱导其对后续脂多糖给药产生不应性（耐受性）。为了研究脂多糖下调其自身细胞因子合成诱导的机制以及IL-6和TNF产生之间的关系，我们试图用如佛波酯（PMA）或γ干扰素（IFN-γ）等试剂来逆转IL-6和TNF产生的抑制，此前有报道称这些试剂可激活巨噬细胞产生细胞因子。用PMA预处理（4微克，在脂多糖给药前10分钟）可部分恢复给予2微克脂多糖的脂多糖耐受小鼠的IL-6产生。另一方面，即使给予高剂量脂多糖（高达200微克），PMA也不能恢复脂多糖耐受小鼠的TNF诱导。在基因上对脂多糖耐药的C3H/HeJ小鼠中也观察到PMA对脂多糖诱导IL-6（而非TNF）的抗性有类似的逆转。IFN-γ也能恢复IL-6的产生，尽管程度比PMA小。然而，与PMA不同的是，IFN-γ也能部分恢复脂多糖耐受小鼠的TNF产生，尽管只有在给予高剂量脂多糖时才会如此。与PMA相比，IFN-γ在恢复TNF合成方面明显比恢复IL-6合成更活跃。在基因上对脂多糖无反应的C3H/HeJ小鼠中也获得了类似结果。这些数据表明，脂多糖耐受小鼠中IL-6和TNF合成的抑制涉及不同机制，且这种抑制的一部分可被PMA或IFN-γ克服。
