PDF(Pubmed)
Abstract：
Although chronic low-grade inflammation does not cause immediate clinical symptoms, over the longer term, it can enhance other insults or age-dependent damage to organ systems and thereby contribute to age-related disorders, such as respiratory disorders, heart disease, metabolic disorders, autoimmunity, and cancer. However, the molecular mechanisms governing low-level inflammation are largely unknown. We discovered that Bcl-2-interacting killer (Bik) deficiency causes low-level inflammation even at baseline and the development of spontaneous emphysema in female but not male mice. Similarly, a single nucleotide polymorphism that reduced Bik levels was associated with increased inflammation and enhanced decline in lung function in humans. Transgenic expression of Bik in the airways of Bik-deficient mice inhibited allergen- or LPS-induced lung inflammation and reversed emphysema in female mice. Bik deficiency increased nuclear but not cytosolic p65 levels because Bik, by modifying the BH4 domain of Bcl-2, interacted with regulatory particle non-ATPase 1 (RPN1) and RPN2 and enhanced proteasomal degradation of nuclear proteins. Bik deficiency increased inflammation primarily in females because Bcl-2 and Bik levels were reduced in lung tissues and airway cells of female compared with male mice. Therefore, controlling low-grade inflammation by modifying the unappreciated role of Bik and Bcl-2 in facilitating proteasomal degradation of nuclear proteins may be crucial in treating chronic age-related diseases.
摘要：
虽然慢性低度炎症不会立即引起临床症状，从长远来看，可以增强对器官系统的其他损害或年龄依赖性损害，从而导致与年龄有关的疾病，如呼吸系统疾病，心脏病,代谢紊乱，自身免疫,和癌症。然而,低水平炎症的分子机制尚不清楚.我们发现，即使在基线时，Bik缺乏症也会导致低水平的炎症，并且在雌性而不是雄性小鼠中自发性肺气肿的发展。同样，降低Bik水平的单核苷酸多态性与人类炎症增加和肺功能下降增强相关.Bik在Bik缺陷小鼠气道中的转基因表达抑制了过敏原或LPS诱导的肺部炎症，并逆转了雌性小鼠的肺气肿。Bik缺乏症增加细胞核但不增加细胞溶质p65水平，因为Bik通过修饰Bcl-2的BH4结构域与Rpn1和Rpn2相互作用，并增强了核蛋白的蛋白酶体降解。Bik缺乏症主要在雌性小鼠中增加炎症，因为与雄性小鼠相比，雌性小鼠的肺组织和气道细胞中的Bcl-2和Bik水平降低。因此,通过改变Bik和Bcl-2在促进核蛋白的蛋白酶体降解中的未被理解的作用来控制低度炎症可能在治疗慢性年龄相关疾病中至关重要.
