Chronic inflammation and susceptibility to bacterial infections in mice lacking the polypeptide (p)105 precursor (NF-κB1) but expressing p50
Chronic inflammation and susceptibility to bacterial infections in mice lacking the polypeptide (p)105 precursor (NF-κB1) but expressing p50
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DOI：
10.1084/jem.187.7.985
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发表时间：
1998-04-06
影响因子：
15.3
通讯作者：
Bravo, R
中科院分区：
文献类型：
--
作者：
Ishikawa, H;Claudio, E;Bravo, R
多肽（p）50分子是核因子（NF）-κ B的亚基，在p105前体（NF-κ B1）的蛋白水解加工后产生。尽管p105前体被假定在调节Rel/NF-κ B活性中发挥作用，但其生理相关性仍不清楚。为了研究这一点，我们产生了缺乏p105前体的COOH末端的一半，但表达p50产物（p105（-/-））的突变小鼠。这些突变小鼠表现出由肺和肝中的淋巴细胞浸润组成的炎性表型，以及对机会性感染的易感性增加。在p105（-/-）小鼠中还观察到多个淋巴结肿大、红细胞髓外造血引起的脾肿大和淋巴样增生。p105（-/-）巨噬细胞的细胞因子产生严重受损，而p105（-/-）B细胞的增殖反应增加。突变小鼠的T细胞功能仅中度受损。p105的缺失也分别导致未刺激和刺激细胞中组成型p50同源二聚体和诱导型NF-κ B活性增强。由于受Rel/NF-κ B调控的几个基因在p105（-/-）胸腺中上调，但在p105（-/-）巨噬细胞中下调，增强的p50同源二聚体似乎作为转录激活因子或抑制因子发挥作用，从而保护细胞类型。因此，p105前体在p50活性的控制中是必不可少的，并且缺乏前体对不同的细胞具有不同的影响。
The polypeptide (p)50 molecule, a subunit of nuclear factor (NF)-kappa B, is produced after proteolytic processing of the p105 precursor (NF-kappa B1). Although the p105 precursor has been postulated to play a role in the regulation of the Rel/NF-kappa B activity, its physiological relevance remains unclear. To investigate that, we generated mutant mice lacking the COOH terminal half of the p105 precursor, but expressing the p50 product (p105(-/-)). These mutant mice displayed an inflammatory phenotype composed of lymphocytic infiltration in lungs and liver, and an increased susceptibility to opportunistic infections. Enlargement of multiple lymph nodes, splenomegaly due to erythrocytic extramedullary hematopoiesis, and lymphoid hyperplasia were also observed in p105(-/-) mice. Cytokine production in p105(-/-) macrophages was severely impaired, whereas proliferative responses of p105(-/-) B cells were increased. T cell functions were only moderately impaired in mutant mice. Loss of p105 also led to enhanced constitutive p50 homodimer and inducible NF-kappa B activities in unstimulated and stimulated cells, respectively. As several genes regulated by Rel/NF-kappa B were upregulated in p105(-/-) thymus but downregulated in p105(-/-) macrophages, the enhanced p50 homodimers appear to function as transcriptional activators or repressors, defending on the cell type. Thus, the p105 precursor is indispensable in the control of p50 activity, and lack of the precursor has distinct effects on different cells.