Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women of childbearing age. Although sex hormones have been implicated in gender bias of the development of this disease, molecular mechanisms remain largely unknown. Elucidation of the role of SLE susceptibility genes, expression of which is regulated by sex hormones, is important to understand the development of the disease. Characterization of the B6.Nba2 lupus prone congenic mice and functional analysis has revealed a previously unknown role for the interferon (IFN)-activatable Ifi202 gene in SLE susceptibility. The major objectives of the proposed studies are to understand the gender-specific increased expression of Ifi202 gene in certain lupus prone strains of mice and to define the role of the encoded phosphoprotein, p202, in the development of lupus susceptibility. The protein p202 (52-kDa) is an inducible (inducible by type-I IFN and interleukin-6) transcriptional modulator with demonstrated ability to inhibit cell cycle progression and apoptosis. Based on our preliminary and other observations, we hypothesize that gender-specific and genetic factors contribute to increased expression of p202 in certain lupus-prone strains of mice. Moreover, we postulate that p202 contributes to lupus susceptibility by increasing the threshold for apoptosis in B and T cells by inhibiting the transcriptional activity of proapoptotic factors, such as E2F and p53.
Aim #1 : To determine how gender-specific and genetic factors contribute to increased expression of p202. We will compare expression of Ifi202 mRNA and protein between age-matched male and female mice (B6, NZB, and B6.Nba2 strains of mice), male and ovariectomized female mice, and estrogen or placebo treated orchiectomized male and female mice. Additionally, we will determine (i) how estrogen (E2) levels through estrogen receptor activate the transcription of the Ifi202; (ii) whether E2-mediated posttranscriptional mechanisms, such as Ifi202 mRNA and protein stabilization, contribute to up-regulation of p202; and (iii) whether nucleocytoplasmic distribution of p202 and its phosphorylation depend on the gender, levels of type-I interferons (alpha and beta), or interleukin-6.
Aim #2 : To investigate whether increased levels of p202 in splenocytes (from male and female mice) correlate with inhibition of the transcriptional activity of E2Fs (E2F1 and E2F2), down-regulation of the expression of the E2F target genes, and defects in activation-induced cell death of CD4+ T cells.
Aim #3 : To elucidate the molecular mechanisms by which increased expression of p202 in splenocytes (from male and female mice) inhibits p53-mediated transcriptional activation and repression of genes, and p53-mediated apoptosis. Significance: Our studies will identify molecular mechanisms by which gender-specific increased expression of p202 in cells of the immune system contributes to lupus susceptibility in a mouse model of lupus.
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