Role of STAT1 and SOCS in Dendritic cell Differentiation

在这项研究中，我们表明STAT通路的激活是发育调节的，并在树突状细胞(DC)的分化和成熟中发挥作用。STAT6信号通路在未成熟DC(IDC)中被结构性激活，并随着IDC分化为成熟DC(MDCs)而减弱。然而，在DC分化过程中，这一途径的下调伴随着细胞因子信号转导抑制物1(SOCS1)、SOCS2、SOCS3和CIS(细胞因子诱导的SH2蛋白)表达的显著诱导，这表明DC成熟可能需要抑制STAT6信号转导。相反，STAT1信号在MDCS中最强，并且不受上调的SOCS蛋白的抑制，表明STAT1和STAT6信号通路在成熟DC中受到明显调控。此外，DC成熟过程中STAT1的最佳激活需要IL-4和GM-CSF，这表明这两种细胞因子的协同作用可能部分地为DC成熟提供了必要的STAT1信号强度。对STAT1-/-DC的分析表明，STAT1在抑制前体DC中CD86的表达，上调MDCs中CD40、CD11c和SOCS1的表达方面发挥了作用。我们进一步证明了IL-4和GM-CSF对DC中SOCS蛋白的诱导有差异：SOCS1主要由IL-4通过STAT1依赖机制诱导，而SOCS3主要由GM-CSF诱导。综上所述，这些结果表明，细胞因子诱导的DC的成熟受到SOCS蛋白的反馈调节，从IDCs中STAT6途径的组成性激活到MDC中主要利用STAT1信号的转换部分是由STAT1诱导的SOCs表达介导的。

In this study we show that activation of STAT pathways is developmentally regulated and plays a role in dendritic cell (DC) differentiation and maturation. The STAT6 signaling pathway is constitutively activated in immature DC (iDC) and declines as iDCs differentiate into mature DCs (mDCs). However, down-regulation of this pathway during DC differentiation is accompanied by dramatic induction of suppressors of cytokine signaling 1 (SOCS1), SOCS2, SOCS3 and CIS (cytokine-induced SH2-containing protein) expression, suggesting that inhibition of STAT6 signaling may be required for DC maturation. In contrast, STAT1 signaling is most robust in mDCs and is not inhibited by the up-regulated SOCS proteins, indicating that STAT1 and STAT6 pathways are distinctly regulated in maturing DC. Furthermore, optimal activation of STAT1 during DC maturation requires both IL-4 and GM-CSF, suggesting that synergistic effects of both cytokines may, in part, provide the requisite STAT1 signaling intensity for DC maturation. Analyses of STAT1-/- DCs reveal a role of STAT1 in repressing CD86 expression in precursor DCs (pDCs) and up-regulating CD40, CD11c and SOCS1 expression in mDCs. We further show that SOCS proteins are differentially induced by IL-4 and GM-CSF in DCs: SOCS1 is primarily induced by IL-4 through a STAT1-dependent mechanism while SOCS3 is induced mainly by GM-CSF. Taken together, these results suggest that cytokine-induced maturation of DCs is under feedback regulation by SOCS proteins and that the switch from constitutive activation of the STAT6 pathway in iDCs to predominant utilization of STAT1 signals in mDC is mediated in part by STAT1-induced SOCS expression.