Cauwels A, Brouckaert P, Grooten J, Huang S, Aguet M, Fiers W
Laboratory of Molecular Biology, University of Ghent, Belgium.
J Immunol. 1995 Mar 15;154(6):2753-63.
In healthy mice, murine (m) TNF is fairly lethal, whereas human (h) TNF (a selective murine TNF-R55 agonist) is rather harmless. However, we and others observed that mice suffering from a bacterial infection, such as Bacillus Calmette-Guérin (BCG), or bearing i.m. some types of tumor, develop a hypersensitivity to the IL-6-inducing and lethal properties of hTNF. This is a cardinal problem as it severely limits the potential use of hTNF-R55-specific agonists for systemic treatment of human cancer. Using mice carrying a targeted disruption in the gene encoding the IFN-gamma receptor (IFN-gamma Ro/o), we here report that endogenous IFN-gamma plays a crucial role in the development of TNF hypersensitivity during BCG infection. Indeed, both the lethality and the IL-6 induced by hTNF were drastically reduced in IFN-gamma Ro/o mice as compared with control mice. These results demonstrate that the enhancement of TNF effects is at least an equally important mechanism by which IFN-gamma contributes to BCG-induced hypersensitivity as the previously described augmentation of TNF production. Experiments in athymic nude mice, either depleted of NK cells or not, revealed that the latter cell population is an important source of the sensitizing IFN-gamma during BCG infection. In contrast, IFN-gamma Ro/o mice were as susceptible as control mice to the sensitizing effects of tumors. mTNF, which interacts with both mTNF-R55 and mTNF-R75 and causes lethality on its own, is as toxic in IFN-gamma Ro/o mice as in wt control mice; this means that TNF-induced IFN-gamma does not play a role in mTNF-induced lethality.
在健康小鼠中，鼠源（m）肿瘤坏死因子（TNF）具有相当大的致死性，而人源（h）TNF（一种选择性鼠源TNF - R55激动剂）则相对无害。然而，我们和其他人观察到，患有细菌感染（如卡介苗（BCG））或在肌肉内接种某些类型肿瘤的小鼠，会对hTNF的白细胞介素 - 6诱导和致死特性产生超敏反应。这是一个关键问题，因为它严重限制了hTNF - R55特异性激动剂在人类癌症全身治疗中的潜在应用。利用携带干扰素 - γ受体（IFN - γR o/o）编码基因靶向破坏的小鼠，我们在此报告内源性IFN - γ在卡介苗感染期间TNF超敏反应的发展中起关键作用。事实上，与对照小鼠相比，hTNF诱导的致死率和白细胞介素 - 6在IFN - γR o/o小鼠中均大幅降低。这些结果表明，TNF效应的增强至少是IFN - γ促成卡介苗诱导的超敏反应的同等重要机制，就如同先前描述的TNF产生增加一样。在无胸腺裸鼠中进行的实验，无论是否清除自然杀伤（NK）细胞，都表明后者细胞群体是卡介苗感染期间致敏性IFN - γ的重要来源。相比之下，IFN - γR o/o小鼠对肿瘤的致敏作用与对照小鼠一样敏感。mTNF与mTNF - R55和mTNF - R75都相互作用并自身导致致死性，在IFN - γR o/o小鼠中与野生型对照小鼠一样具有毒性；这意味着TNF诱导的IFN - γ在mTNF诱导的致死性中不起作用。
