Dysregulation of cytokine expression, especially of IL-2 and IL-17, is a hallmark of misguided immunity in SLE patients. T cells from SLE patients fail to express IL-2, an effect caused by multiple mechanisms. The first mechanism reported to affect IL-2 expression in SLE T lymphocytes is trans-repression at the IL2 gene promoter. CREMα and the activating transcriptional regulatory factor CREB share a cis-regulatory element 180 base pairs upstream of the transcriptional initiation site of IL2 (a site denoted −180CRE). Under physiological conditions, the −180CRE site is constitutively occupied by CREB. Upon T cell activation CREB undergoes phosphorylation, which further increases CREB binding to this site. In T lymphocytes from SLE patients, CREMα replaces CREB, and trans-represses IL2 gene transcription [22,40]. In addition to this trans-repression, CREMα recruits HDAC1 and DNMT-3a to the IL2 promoter, mediating epigenetic remodeling through histone deacetylation and de novo CpG methylation, respectively [41,42]. Similar to CREB, CREMα can bind histone acetyltransferase p300, mediating its recruitment to the IL2 promoter. However, unlike CREB, CREMα lacks a trans-activating domain and fails to activate p300 [41,43]. This contributes to reduced histone acetylation and condensation of the IL2 promoter.
