CAMP responsive element modulator (CREM)α induces epigenetic remodeling of IL2 in T lymphocytes from SLE patients (121.2)

Abstract

Abstract IL-2 functions as an auto- and paracrine growth-factor for T lymphocytes and is essential during their proliferation and activation. The absence of IL-2 has been linked to the development of autoimmune phenotypes in mice and humans. The multi-factorial autoimmune disease Systemic lupus erythematosus (SLE) is characterized by disrupted transcription factor networks and dysregulated cytokine expression, antigen-presentation, and lymphocyte function. The failure to express IL-2 is a hallmark of SLE T lymphocytes and results in reduced numbers of regulatory T lymphocytes that prevent autoimmunity. Impaired IL-2 expression was linked to over-production of the transcription regulatory factor cAMP response element modulator (CREM)α that in turn binds to a CRE site within the IL2 promoter (-180 CRE) in SLE T lymphocytes. Here, we document the involvement of CREMα mediated gene-wide HDAC1-directed deacetylation of histone H3K18, and DNMT3a directed CpG-DNA hypermethylation in the silencing of IL2 in T lymphocytes from SLE patients. We provide evidence that CREMα mediates silencing of IL2 in SLE T cells through histone deacetylation, and CpG-DNA methylation. Our findings add further evidence to the discussion of whether epigenetic modifications display region and tissue-specific patterns in health and disease. Thus, CREMα may serve as a promising target to correct cytokine expression in patients with SLE.