Systemic lupus erythematosus (SLE) is an autoimmune disorder of largely unknown etiology characterized by profound T cell effector dysfunction. SLE T cells produced reduced amounts of interleukin 2 (IL-2) which contributes to the increased rate of infections, decreased generation of cytotoxic and regulatory T cells and decreased ability to eliminate autoreactive T cells through activation-induced cell death. IL-2 production is controlled at the transcription level by factors whose activity is influenced by membrane-initiated signaling events. We established that SLE T cells have increased protein and mRNA levels of the transcriptional repressor, cAMP responsive element modulator (CREM), which we found to bind to the -180 site of the IL-2 promoter and suppress IL-2 gene transcription. CREM also binds to the -57 site of the c-fos promoter which results in decreased expression of c-fos protein and activating protein-1 activity. Normal, unstimulated T cells do not express CREM, but after stimulation they display phosphorylated (p) cAMP responsive element binding protein (CREB) that binds also to the -180 site. We also demonstrated that anti-CD3/TCR autoantibodies activate calcium/calmodulin kinase IV (CaMKIV) which is found primarily in the nucleus where it phosphorylates CREM and histones. CREM recruits histone deacetylase 1 (HDAC1) to the promoters of the IL-2 and c-fos genes which contributes to the repression of their activity. Increased expression of CREM? in SLE T cells represents both increased promoter (newly characterized) activity and alternative splicing. It is hypothesized that cell membrane-initiated signaling processes lead to increased expression and activation of transcription repressors and modification of cellular proteins. We propose, accordingly, to a) establish that CaMKIV translocates to the nucleus of SLE T cells, determine how it becomes activated and whether its presence is crucial in the development of SLE in lupus prone mice;b) identify the functional repercussions of CREM? - mediated recruitment of HDAC1 to the regulation - of aberrant gene expression in SLE T cells, the identification of novel CREM target genes and whether its absence modifies the expression of SLE in lupus-prone mice;and c) determine mechanisms that result in increased production of CREM1 in SLE T cells, that is, increased promoter activity and enhanced alternative exon splicing process. The proposed studies will provide further insights into the molecular origin of defective IL-2 production in SLE patients and identify molecular targets that may be corrected with drugs or biologics. Successful completion will introduce additional mechanisms that lead to the generation of autoantigens that drive autoimmunity.
- PROJECT NARRATIVE: Systemic lupus erythematosus (SLE) afflicts more than one million Americans most of whom are women in the child bearing age. Immune cells from patients with SLE produce decreased production of interleukin-2 and that leads to increased rate on infections and accounts for additional immunoregulatory defects. The proposed studies will explore the mechanisms that lead to decreased production of interleukin-2 in order to identify molecules that we can target for therapeutic purposes.
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