Regulation of the Immune response by CREM

吞噬功能缺陷是系统性红斑狼疮（SLE）发病机制中的重要标志。我们发现转录抑制因子CREMα在SLE患者的B细胞和单核细胞中大量表达。CREMα与含有cAMP反应元件（CRE）的基因启动子结合，并以染色质依赖性机制负调控其转录。通过ChIP on Chip启动子分析，我们鉴定了CREM结合LPS处理的人单核细胞中的1807个基因，包括吞噬作用的调节因子。此外，CREM-/-和CREMα转基因小鼠在体外显示出吞噬作用水平的改变。因此，我们认为CREMα改变了单核细胞的吞噬功能，这与SLE有关。为了验证这一点，我们将扩大我们对CREM-/-和CREMα转基因小鼠的体外和体内吞噬作用的研究。其次，我们将使用这些小鼠来分析吞噬相关基因的基因表达，这些基因是通过ChIP on Chip分析鉴定的。第三，我们将我们的研究结果扩展到SLE患者，通过si-RNA敲低CREMα以恢复吞噬功能。拟议的研究将揭示单核细胞中CREMα对吞噬作用和免疫反应的分子调节以及新疗法的新见解。

Defects in phagocytosis are of hallmark importance in the pathogenesis of systemic lupus erythematosus (SLE). We found that the transcriptional repressor CREMα is heavily expressed in B cells and monocytic cells from patients with SLE. CREMα binds to promoters of genes that contain cAMP response elements (CRE) and negatively regulates their transcription in a chromatin-dependent mechanism. By ChIP on Chip promoter analysis we identified CREM binding to 1807 genes in LPS treated human monocytic cells including regulators of phagocytosis. Moreover CREM-/- and CREMα transgenic mice show altered levels of phagocytosis in vitro. We thus propose that CREMα alters phagocytic functions in monocytic cells and that this is of relevance for SLE. To test this we will expand our studies on in vitro and in vivo phagocytosis in CREM-/- and CREMα transgenic mice. Second, we will use these mice to analyze gene expression of phagocytosis relevant genes, which were identified by ChIP on Chip analysis. Third we will extend our findings towards patients with SLE and knock down CREMα by si-RNA to restore phagocytotic functions. The proposed studies will reveal new insights in the molecular regulation of phagocytosis and of the immune response by CREMα in monocytes and into approaches for new therapies.