PDF(Pubmed)
Abstract：
A pleiotropic immunoregulatory cytokine, TGF-β, signals via the receptor-regulated SMADs: SMAD2 and SMAD3, which are constitutively expressed in normal cells. Here, we show that selective repression of SMAD3 induces cDC differentiation from the CD115+ common DC progenitor (CDP). SMAD3 was expressed in haematopoietic cells including the macrophage DC progenitor. However, SMAD3 was specifically down-regulated in CD115+ CDPs, SiglecH- pre-DCs, and cDCs, whereas SMAD2 remained constitutive. SMAD3-deficient mice showed a significant increase in cDCs, SiglecH- pre-DCs, and CD115+ CDPs compared with the littermate control. SMAD3 repressed the mRNA expression of FLT3 and the cDC-related genes: IRF4 and ID2. We found that one of the SMAD transcriptional corepressors, c-SKI, cooperated with phosphorylated STAT3 at Y705 and S727 to repress the transcription of SMAD3 to induce cDC differentiation. These data indicate that STAT3 and c-Ski induce cDC differentiation by repressing SMAD3: the repressor of the cDC-related genes during the developmental stage between the macrophage DC progenitor and CD115+ CDP.
摘要：
多效免疫调节细胞因子，TGF-β,信号通过受体调节的SMADs：SMAD2和SMAD3，它们在正常细胞中组成型表达。这里,我们显示SMAD3的选择性抑制诱导cDC从CD115+普通DC祖细胞(CDP)分化。SMAD3在包括巨噬细胞DC祖细胞的造血细胞中表达。然而,SMAD3在CD115+CDP中特异性下调，Siglech-pre-DC,和cDC，而SMAD2保持构成性。SMAD3缺陷小鼠显示cDCs显著增加,Siglech-pre-DC,和CD115+CDP与同窝窝对照相比。SMAD3抑制FLT3和cDC相关基因IRF4和ID2的mRNA表达。我们发现SMAD转录抑制因子之一，c-SKI,在Y705和S727与磷酸化STAT3合作抑制SMAD3的转录以诱导cDC分化。这些数据表明STAT3和c-Ski通过抑制SMAD3诱导cDC分化:在巨噬细胞DC祖细胞和CD115+CDP之间的发育阶段期间cDC相关基因的阻遏物。
