Category: Autoimmune rheumatologic diseases
Systemic lupus erythematosus (SLE) is a chronic debilitating autoimmune disease that primarily afflicts women in the childbearing years. Female hormones especially estrogen are implicated in disease pathogenesis, yet the precise molecular events regulated by estrogen in immune cells are not clear. We previously showed that the expression levels of serine/arginine-rich splicing factor (SRSF)1 are decreased in T cells from SLE patients and associate with severe disease activity. We recently generated T cell conditional Srsf1-deficient mice, which exhibit T cell hyperactivity, aberrant cytokine production and develop lupus-like disease. These studies imply that SRSF1 is an important molecule in T cell function and its deficiency contributes to autoimmune disease. Yet, little is known of the regulation of SRSF1 in T cells. We hypothesized that estrogen may regulate SRSF1 expression in human T cells. We found that exposure to estrogen led to a dose dependent increase in Srsf1 mRNA levels but a decrease in protein levels in human T cells. This discrepancy between mRNA and protein levels suggests that estrogen controls SRSF1 via multiple mechanisms. Accordingly estrogen increased the activity of an Srsf1-promoter-luciferase construct indicating that estrogen activates transcription of Srsf1. In parallel, the addition of the proteasome inhibitor MG132 to estrogen-treated cells rescued SRSF1 protein levels, indicating that estrogen leads to proteasome-mediated degradation of SRSF1. Our results suggest that estrogen can modulate the expression of SRSF1 via transcriptional and post-transcriptional mechanisms in human T lymphocytes, thus revealing a potential molecular link between hormones, immune cells and autoimmune disease.
Melissa Carr-Reynolds– Research Assistant, Beth Israel Deaconess Medical Center, Harvard Medical School
Julian F Oviedo– Student, Beth Israel Deaconess Medical Center, Harvard Medical School
Elena N Cravens– Student, Beth Israel Deaconess Medical Center, Harvard Medical School
Vaishali Moulton– Assistant Professor, Beth Israel Deaconess Medical Center, Harvard Medical School