Regulation of the Immune response by CREM

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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.