cAMP-responsive Element Modulator (CREM)α Protein Signaling Mediates Epigenetic Remodeling of the Human Interleukin-2 Gene IMPLICATIONS IN SYSTEMIC LUPUS ERYTHEMATOSUS

IL-2 is a key cytokine during proliferation and activation of T lymphocytes and functions as an auto-and paracrine growth factor. Regardless of activating effects on T lymphocytes, the absence of IL-2 has been linked to the development of autoimmune pathology in mice and humans. Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease and characterized by dysregulation of lymphocyte function, transcription factor and cytokine expression, and antigen presentation. Reduced IL-2 expression is a hallmark of SLETlymphocytes and results in decreased numbers of regulatory T lymphocytes which play an important role in preventing autoimmunity. Reduced IL-2 expression was linked to overproduction of the transcription regulatory factor cAMP-responsive element modulator (CREM)alpha in SLE T lymphocytes and subsequent CREM alpha binding to a CRE site within the IL2 promoter (-180 CRE). In this study, we demonstrate the involvement of CREM alpha-mediated IL2 silencing inTlymphocytes from SLE patients through a gene-wide histone deacetylase 1-directed deacetylation of histone H3K18 and DNA methyltransferase 3a-directed cytosine phosphate guanosine (CpG)-DNA hypermethylation. For the first time, we provide direct evidence that CREM alpha mediates silencing of the IL2 gene in SLE T cells though histone deacetylation and CpG-DNA methylation.