Brief Report: Autocrine Cytokine–Mediated Deficiency of TRAIL‐Induced Monocyte Apoptosis in Rheumatoid Arthritis
Brief Report: Autocrine Cytokine–Mediated Deficiency of TRAIL‐Induced Monocyte Apoptosis in Rheumatoid Arthritis
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简要报告：自分泌细胞因子â介导的TRAILâ缺乏诱导类风湿性关节炎中的单核细胞凋亡
DOI：
10.1002/art.39138
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发表时间：
2015
影响因子：
13.3
通讯作者：
Wagner U
中科院分区：
文献类型：
--
作者：
Meusch U;Klingner M;Mathar C;Malysheva O;Baerwald C;Rossol M;Wagner U
单核细胞凋亡失调是类风湿关节炎（RA）的一个致病特征。本研究的目的是探讨TRAIL和TRAIL诱导的细胞凋亡在RA患者中的作用。方法测定63例RA患者的细胞表面表达和血清中TRAIL的浓度，并对TRAIL诱导的单核细胞凋亡进行定量。测定TRAILR-1、TRAILR-2、TRAILR-3、TRAILR-4、CXCR 1和CXCR 2的表面表达，并研究细胞内信号转导。在8例RA患者中，疾病活动的临床和实验室参数进行了纵向研究，肿瘤坏死因子（TNF）inhibitors.ResultsSerum浓度的TRAIL和白细胞介素-8（IL-8）的治疗开始之前和之后，RA患者增加，而细胞表面表达的TRAIL受体TRAILR-1，TRAILR-2，TRAILR-3，和TRAILR-4减少。由于RA单核细胞的TRAIL诱导的IL-8分泌增加，RA中TRAIL诱导的单核细胞凋亡显著减少。TRAIL和IL-8对单核细胞的联合作用导致抗凋亡途径的激活，包括p42/44 MAPK和p38。TNF inhibition.ConclusionIn RA，循环单核细胞具有产生促炎细胞因子的潜力，在几种凋亡诱导途径中存在缺陷，其中之一是缺乏TRAIL诱导的凋亡。尽管这种对细胞凋亡的抵抗可能有助于疾病的持续，但仍有待确定细胞凋亡的特异性诱导是否在治疗上有益。
ObjectiveDysregulated apoptosis of monocytes is a pathogenic feature of rheumatoid arthritis (RA). The aim of this study was to investigate the role of TRAIL and TRAIL‐induced apoptosis in patients with RA.MethodsCell surface expression and serum concentrations of TRAIL were determined in 63 patients with RA, and TRAIL‐induced monocyte apoptosis was quantified. Surface expression of TRAILR‐1, TRAILR‐2, TRAILR‐3, TRAILR‐4, CXCR1, and CXCR2 was determined, and intracellular signal transduction was investigated. In 8 patients with RA, clinical and laboratory parameters of disease activity were investigated longitudinally, before and after initiation of treatment with tumor necrosis factor (TNF) inhibitors.ResultsSerum concentrations of both TRAIL and interleukin‐8 (IL‐8) were increased in patients with RA, while cell surface expression of the TRAIL receptors TRAILR‐1, TRAILR‐2, TRAILR‐3, and TRAILR‐4 was diminished. TRAIL‐induced monocyte apoptosis was significantly decreased in RA due to increased TRAIL‐induced IL‐8 secretion by RA monocytes. The combined effect of TRAIL and IL‐8 on monocytes resulted in activation of antiapoptotic pathways, including p42/44 MAPK and p38. Susceptibility to TRAIL‐induced apoptosis was restored in RA monocytes after 3 months of TNF inhibition.ConclusionIn RA, circulating monocytes with the potential to produce proinflammatory cytokines appear to have defects in several pathways of apoptosis induction, among which is a deficiency in TRAIL‐induced apoptosis. Although this resistance to apoptosis might contribute to perpetuation of the disease, it remains to be determined whether specific induction of apoptosis could be therapeutically beneficial.