Abstract
Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6–STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+ T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4+ T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner.
Highlights
Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM)
Using western blotting we investigated the expression of CREM isoform induction in ICER/ CREM-sufficient and -deficient T cells cultured under Th17-polarizing conditions
We noted a o20 kDa CREM band to be induced by day 3 (Fig. 1a, left) in ICER/CREM-sufficient but not in ICER/CREM-deficient T cells (Fig. 1a, right first and second lanes) pointing that this band was an isoform of CREM
Summary
Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. We find ICER overexpressed in CD4 þ T cells from patients with systemic lupus erythematosus. Numerous reports have claimed that interleukin (IL)-17 has an important role in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus (SLE)[1,3,4,5]. Previous papers have shown that ICER inhibits T-cell activation, Th1/Th2 cell differentiation and suppresses the production of proinflammatory cytokines[10,11]; whether ICER is involved in the generation of Th17 cells is not known
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