In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment
In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment
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DOI：
10.1182/blood-2003-02-0518
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发表时间：
2003-12-01
期刊：
影响因子：
20.3
通讯作者：
Taoufik, Y
中科院分区：
文献类型：
--
作者：
Durali, D;de Herve, MGD;Taoufik, Y
最近已经鉴定了产生Th1和Th2样细胞因子模式的两种功能不同的B细胞亚群。白细胞介素-12（IL-12）是一种重要的免疫调节细胞因子，通过激活信号转导子和转录激活子4（STAT4）促进Th1细胞分化。据报道IL-12可诱导B细胞产生干扰素γ（IFN-γ），但相关的信号传导途径缺乏文献记载。在这里，在人类原代B细胞中，我们发现了一种功能性IL-12受体（IL-12 R），其在IL-12结合后内化。IFN-γ和IL-12在较小程度上正调节IL-12R β 2亚基，但对IL-12R β 1没有影响。在检查IL-12对STAT4和T-bet（参与IFN-γ启动子激活的2个关键因子）的作用时，我们发现IL-12诱导STAT4的磷酸化和核转位。在自发产生IL-12的EB病毒（EBV）转化的B细胞系RPMI 8866中也观察到IL-12依赖性组成型STAT4活化。T-bet的表达依赖于STAT1。IL-12对原代B细胞中的STAT1活化或T-bet表达没有直接影响。相反，IL-12诱导的IFN-γ导致STAT1活化、T-bet的强表达和IFN-γ表达。因此，IL-12在B细胞中启动级联事件，包括STAT 4活化、IL-12 R β 2上调、IFN-γ产生和T-bet上调，潜在地导致Th1样分化。(C)2003年，美国血液学会。
Two functionally distinct subsets of B cells that produce Th1- and Th2-like patterns of cytokines have recently been identified. Interleukin-12 (IL-12) is a critical immunoregulatory cytokine that promotes Th1 differentiation through activation of signal transducer and activator of transcription 4 (STAT4). IL-12 has been reported to induce interferon gamma (IFN-gamma) production in B cells, but the relevant signaling pathways ate poorly documented. Here, in human primary B cells, We found a functional IL-12 receptor (IL-12R) that internalizes following IL-12 binding. IFN-gamma and, to a lesser extent, IL-12 positively regulated the IL-12Rbeta2 subunit but had no effect on IL-12Rbeta1. On examining the effect of IL-12 on STAT4 and T-bet (2 key factors involved in IFN-gamma promoter activation), we found that IL-12 induced the phosphorylation and nuclear translocation of STAT4. IL-12-dependent constitutive STAT4 activation was also observed in the Epstein-Barr virus (EBV)-transformed B-cell line RPMI 8866 that spontaneously produces IL-12. T-bet expression has been shown to be dependent on STAT1.. IL-12 had no direct effect on STAT1 activation or T-bet expression in primary B cells. In contrast, IL-12-induced IFN-gamma led to STAT1 activation, strong expression of T-bet, and IFN-gamma expression. IL-12 therefore initiates a cascade of events in B cells, including STAT4 activation, IL-12Rbeta2 up-regulation, IFN-gamma production, and T-bet up-regulation, potentially leading to Th1-like differentiation. (C) 2003 by The American Society of Hematology.