The role of cell type-specific responses in IFN-β therapy of multiple sclerosis
The role of cell type-specific responses in IFN-β therapy of multiple sclerosis
复制标题
DOI：
10.1073/pnas.1117347108
复制
发表时间：
2011-12-06
影响因子：
11.1
通讯作者：
van Boxel-Dezaire, Anette H. H.
中科院分区：
文献类型：
--
作者：
Zula, Joana A.;Green, Holly C.;van Boxel-Dezaire, Anette H. H.
IFN-β治疗复发-缓解型多发性硬化症（RRMS）的机制还不清楚，但诱导特定白细胞亚群的凋亡可能很重要。已提出未分离白细胞中TNFSF 10或TNF相关凋亡诱导配体（TRAIL）mRNA的表达增强作为治疗反应标志物，但尚不清楚哪些白细胞亚群表达TRAIL。我们通过研究RRMS患者不同白细胞亚群中STATs 1、3和5、p38 MAPK和NF-κ B的活化，研究了TRAIL表达对IFN-β应答的基础。单核细胞、B细胞和T细胞对i. M.注射IFN-β 1a或体外刺激。在9个白细胞亚群中分析的细胞表面TRAIL的诱导仅在单核细胞和粒细胞上观察到，并且仅在这些亚群中与p38和/或NF-κ B B的活化相关，这与先前在成纤维细胞中的工作一致，所述工作显示响应于IFN-β的TRAIL的诱导依赖于p38和NF-κ B B以及STAT 1和2的活化。我们认为，在骨髓细胞中，p38和NF-κ B的差异激活和诱导TRAIL，使细胞对凋亡敏感，可以帮助解释RRMS患者对IFN-β治疗反应的差异，此外，这种激活和表达的差异模式也可能对理解肝炎和癌症对IFN-α/β的治疗反应很重要。
The mechanism of IFN-beta therapy in relapsing-remitting multiple sclerosis (RRMS) is not well understood, but induction of apoptosis in specific leukocyte subsets is likely to be important. Enhanced expression of TNFSF10 or TNF-related apoptosis-inducing ligand (TRAIL) mRNA in unseparated leukocytes has been put forward as a therapeutic response marker, but it is unclear which leukocyte subsets express TRAIL. We investigated the basis of TRAIL expression in response to IFN-beta by studying activation of STATs 1, 3, and 5, p38 MAPK, and NF-.B in different leukocyte subsets of patients with RRMS. Monocytes, B cells, and T cells showed substantial differences in the activation of p38 and the STATs in response to i. m. injection of IFN-beta 1a or stimulation in vitro. Induction of cell-surface TRAIL, analyzed in nine leukocyte subsets, was observed only on monocytes and granulocytes and correlated with the activation of p38 and/or NF-kappa B in these subsets only, in agreement with previous work in fibroblasts showing that the induction of TRAIL in response to IFN-beta depends on the activation of p38 and NF-.B as well as STATs 1 and 2. We propose that, in myeloid cells, the differential activation of p38 and NF-kappa B and induction of TRAIL, which sensitizes cells to apoptosis, can help to explain differences in responsiveness to IFN-beta therapy among patients with RRMS and, furthermore, that such differential patterns of activation and expression may also be important in understanding the therapeutic responses to IFN-alpha/beta in hepatitis and cancer.