Ehlers Mario R
Biol Chem. 2014 Oct;395(10):1187-93. doi: 10.1515/hsz-2014-0161.
Alpha-1 antitrypsin (AAT) is a circulating serine protease inhibitor (serpin) that inhibits neutrophil elastase in the lung, and AAT deficiency is associated with early-onset emphysema. AAT is also a liver-derived acute-phase protein that, in vitro and in vivo, reduces production of pro-inflammatory cytokines, inhibits apoptosis, blocks leukocyte degranulation and migration, and modulates local and systemic inflammatory responses. In monocytes, AAT has been shown to increase intracellular cAMP, regulate expression of CD14, and suppress NFκB nuclear translocation. These effects may be mediated by AAT's serpin activity or by other protein-binding activities. In preclinical models of autoimmunity and transplantation, AAT therapy prevents or reverses autoimmune disease and graft loss, and these effects are accompanied by tolerogenic changes in cytokine and transcriptional profiles and T cell subsets. This review highlights advances in our understanding of the immune-modulating effects of AAT and their potential therapeutic utility.
α-1抗胰蛋白酶（AAT）是一种循环丝氨酸蛋白酶抑制剂（丝氨酸蛋白酶抑制剂），可抑制肺部的中性粒细胞弹性蛋白酶，AAT缺乏与早发性肺气肿有关。AAT也是一种肝脏来源的急性期蛋白，在体外和体内均可减少促炎细胞因子的产生，抑制细胞凋亡，阻止白细胞脱颗粒和迁移，并调节局部和全身炎症反应。在单核细胞中，AAT已被证明可增加细胞内cAMP，调节CD14的表达，并抑制NFκB核转位。这些作用可能由AAT的丝氨酸蛋白酶抑制剂活性或其他蛋白质结合活性介导。在自身免疫和移植的临床前模型中，AAT治疗可预防或逆转自身免疫性疾病和移植物丢失，这些作用伴随着细胞因子和转录谱以及T细胞亚群的致耐受性变化。本综述重点介绍了我们对AAT免疫调节作用及其潜在治疗用途的理解进展。
