Systemic IFN-β treatment induces apoptosis of peripheral immune cells in MS patients
Systemic IFN-β treatment induces apoptosis of peripheral immune cells in MS patients
复制标题
DOI：
10.1016/s0165-5728(03)00074-2
复制
发表时间：
2003-04-01
影响因子：
3.3
通讯作者：
Zipp, F
中科院分区：
文献类型：
--
作者：
Gniadek, P;Aktas, O;Zipp, F
在多发性硬化症（MS）中，活化的中枢神经系统特异性免疫细胞的凋亡缺失受损，导致其致病持久性，已被认为是维持慢性脑炎症的原因。我们在这里研究干扰素- β (ifn - β)治疗是否诱导外周免疫细胞凋亡。在开始每周ifn - β 1a治疗之前，以及之后的4、26和52周，分析了127例复发缓解型MS患者的连续血液样本。采用实时荧光定量PCR技术研究外周免疫细胞凋亡及凋亡调控基因CD95、CD95配体、FLIP、Bcl-2、BCI-X-L、Bag-1和caspase 3的表达情况。通过Mx的定量表达（ELISA和real-time PCR）检测ifn - β治疗的生物学效果。我们发现，与基线水平相比，ifn - β治疗后免疫细胞的凋亡率显著增加。治疗后，Bcl-2水平永久升高，Bag-1水平短暂升高，而其他凋亡调节基因没有变化。Mx表达上调证实了体内ifn - β的活性。这些发现表明，免疫调节ifn - β治疗涉及通过观察到的Bcl-2家族成员RNA上调诱导凋亡细胞死亡，而不是反映可能的补偿机制。在ifn - β治疗期间，外周免疫细胞凋亡易感性的增加可能有助于减少已知的脑炎性病变。(C) 2003 Elsevier Science B.V.版权所有
In multiple sclerosis (MS), an impaired apoptotic deletion of activated CNS-specific immune cells, leading to their pathogenic persistence, has been suggested to maintain chronic brain inflammation. We here investigated whether interferon-beta (IFN-beta) therapy induces apoptosis of peripheral immune cells. Serial blood samples from 127 relapsing-remitting MS patients were analyzed prior to the initiation of a weekly IFN-beta1a therapy and 4, 26, and 52 weeks thereafter. Peripheral immune cells were investigated for apoptosis and for the expression of apoptosis-regulatory genes CD95, CD95 ligand, FLIP, Bcl-2, BCI-X-L, Bag-1, and caspase 3 by quantitative real-time PCR. Biological efficacy of IFN-beta treatment was checked by quantification of Mx expression (ELISA and real-time PCR). We found a significant increase in the apoptosis rate of immune cells in response to IFN-beta treatment, compared to baseline levels. While Bcl-2 levels were permanently and Bag-1 levels transiently elevated upon therapy, other apoptosis-regulatory genes revealed no alterations. Upregulation of Mx expression confirmed the activity of IFN-beta in vivo. These findings indicate that immanomodulatory IFN-beta therapy involves the induction of apoptotic cell death with the observed RNA upregulation of Bcl-2 family members rather reflecting a possible compensatory mechanism. The increased apoptosis susceptibility of peripheral immune cells may contribute to the known reduction of brain inflammatory lesions during IFN-beta treatment. (C) 2003 Elsevier Science B.V. All rights reserved.