Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases.
Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases.
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DOI：
10.1084/jem.20040435
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发表时间：
2004-08-02
期刊：
影响因子：
--
通讯作者：
Kollias G
中科院分区：
文献类型：
--
作者：
Xanthoulea S;Pasparakis M;Kousteni S;Brakebusch C;Wallach D;Bauer J;Lassmann H;Kollias G
肿瘤坏死因子（TNF）是一种有效的细胞因子，在免疫和炎症反应的激活和调节中发挥关键作用。由于其多效性活动，TNF功能的幅度和持续时间必须严格调节。调节TNF功能的机制之一可能是其细胞表面受体的蛋白水解裂解。在人类中，影响p55 TNF受体（R）脱落的突变与TNFR相关周期性综合征的发生有关，该综合征是以反复发热和局部炎症为特征的疾病。在这里，我们表明，敲入小鼠表达突变nonsheddable p55TNFR开发Toll样受体依赖性先天免疫高反应性，这使得他们的免疫系统更有效地控制细胞内细菌感染。值得注意的是，抗菌宿主防御功能的获得是以导致病理学的失衡炎症反应为代价的。突变小鼠表现出自发性肝炎，内毒素休克的易感性增强，TNF依赖性关节炎加重，实验性自身免疫性脑脊髓炎。这些结果为受体脱落引入了一个新的概念，受体脱落是一种建立细胞因子功能阈值的机制，以平衡对疾病的抵抗力和易感性。因此，p55TNFR脱落的评估可能对感染性、炎症性和自身免疫性疾病具有预后价值。
Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor–dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.
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影响因子：
11.4
作者：
KEFFER, J;PROBERT, L;KOLLIAS, G
通讯作者：
KOLLIAS, G
影响因子：
--
作者：
Kriegel, MA;Hüffmeier, U;Lorenz, HM
通讯作者：
Lorenz, HM
影响因子：
4.3
作者：
Pasparakis, M;Kousteni, S;Kollias, G
通讯作者：
Kollias, G
影响因子：
3.8
作者：
LANTZ M;MALIK S;OLSSON I
通讯作者：
OLSSON I
影响因子：
1.6
作者：
Hull, KM;Drewe, E;Kastner, DL
通讯作者：
Kastner, DL