Abstract
BackgroundRecent studies have shown that early growth response 2 (EGR2) is highly induced in activated T cells and regulates T cell functions. In normal C57BL/6 (B6) mice, deletion of EGR2 in lymphocytes results in the development of lupus-like systemic autoimmune disease, which implies indirectly an autoimmune protective role of EGR2. Conversely, increased EGR2 gene expression is suggested to link with high risk of human lupus. In the present studies we sought to clarify the expression and inflammation regulatory role of EGR2 in murine lupus T cells directly.ResultsWe performed RT-qPCR analysis and found a significant increase of EGR2 mRNA expression in human lupus PBMCs and in CD4+ T cells from three different murine lupus models including MRL-lpr, B6-lpr, and B6.sle123 mice at diseased stage when compared to age-matched control MRL or B6 mice. By performing intracellular flow cytometry analysis, we found that EGR2 protein expression was significantly increased in resting lupus (either MRL-lpr or B6.sle123) CD4+ T cells when compared to CD4+ T cells from their respective non-autoimmune controls. However, there was no difference of EGR2 protein expression in anti-CD3 and anti-CD28 stimulated control and lupus CD4+ T cells since there was a stronger induction of EGR2 in activated control CD4+ T cells. EGR2 expression was significantly increased in MRL-lpr mice at an age when lupus is manifested. To understand further the function of elevated EGR2 in lupus CD4+ T cells, we inhibited EGR2 with a specific siRNA in vitro in splenocytes from MRL-lpr and control MRL mice at 15 weeks-of-age. We found that EGR2 inhibition significantly reduced IFNγ production in PMA and ionomycin activated MRL-lpr lupus CD4+ T cells, but not control MRL CD4+ T cells. We also found that inhibition of EGR2 in vitro suppressed the Th1 differentiation in both MRL and MRL-lpr naïve CD4+ T cells.ConclusionsEGR2 is highly upregulated in human and murine lupus cells. Our in vitro data suggest a positive role of EGR2 in the regulation of Th1 differentiation and IFNγ production in lupus effector CD4+ T cells.
Highlights
Recent studies have shown that early growth response 2 (EGR2) is highly induced in activated T cells and regulates T cell functions
We found that EGR2 mRNA expression was significantly higher in human lupus Peripheral blood mononuclear cell (PBMC) than healthy controls (Fig. 1a)
Our data demonstrated a significant increase of EGR2 expression in CD4+ T cells of murine lupus cells when compared to their respective controls
Summary
Recent studies have shown that early growth response 2 (EGR2) is highly induced in activated T cells and regulates T cell functions. In normal C57BL/6 (B6) mice, deletion of EGR2 in lymphocytes results in the development of lupus-like systemic autoimmune disease, which implies indirectly an autoimmune protective role of EGR2. In the present studies we sought to clarify the expression and inflammation regulatory role of EGR2 in murine lupus T cells directly. The non-autoimmune wildtype C57BL/6 (B6) mice with EGR2 deficiency in both T and B cells (CD2-CreEGR2−/−) had late-onset 6 months old) lupus-like autoimmune disease, characterized by an accumulation of highly activated CD4+CD44+ T cells and infiltration of IFNγ- and IL-17- producing CD4+ T cells in multiple organs [5]. To determine the role of EGR2 in T cells, Okamura et al generated T cell specific EGR2 depletion B6 mice (CD4-CreEGR2−/−)
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