title: CREM Alpha Enhances IL-21 Production in T CellsIn VivoandIn Vitro.
abstract: The cAMP-responsive element modulator alpha (CREMα) plays a role in autoimmunity and, in particular, in systemic lupus erythematosus. CREMα negatively regulates IL-2 transcription and activates IL-17 expression by direct transcriptional mechanisms. To understand the role of CREM in autoimmunity, we recently generated a mouse with a transgenic overexpression of CREMα selectively in T cells. This mouse is characterized by enhanced IL-17 and IL-21 expression. We, herein, dissect the transcriptional mechanisms of enhanced IL-21 transcription in these mice. T cells of CREMα transgenic mice display an enhanced binding of CREMα to the CD3ζ chain promoter resulting in decreased CD3ζ chain expression. This is accompanied by a decreased excitation threshold and enhanced Ca2+influx, which is known to induce IL-21 expressionviaNFATc2 activation. However, CREMα directly binds to cAMP-response element (CRE) half-site within theIl-21promoter, which results in enhanced promoter activity shown by promoter reporter assays. CREMα-induced IL-21 transcription is not abrogated in the presence of cyclosporine A but depends on an intact CRE site within the IL-21 promoter, which suggests that CREM largely enhances IL-21 expression by direct transcriptional regulation. IL-21 transcription is critical for IL-17 generation in these mice, since IL-21 receptor blockade downregulates IL-17 transcription to wild-type levels. Finally, this is of functional relevance since CREMα transgenic mice display enhanced disease activity in dextran sodium sulfate-induced colitis accompanied by higher local IL-21 expression. Thus, we describe two novel mechanisms of CREMα-dependent IL-21 transcription. Since T cells of systemic lupus erythematosus patients are characterized by enhanced IL-21 transcription, this might also be of functional relevance in humans.
authors.affiliation: Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany.
authors.forename: Kim
authors.initials: K
authors.lastname: Ohl
authors.affiliation: Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Wiener
authors.affiliation: Institute of Immunology, University of Münster , Münster , Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Lippe
authors.affiliation: Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schippers
authors.affiliation: Institute of Biochemistry and Molecular Immunology, RWTH Aachen University , Aachen , Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Zorn
authors.affiliation: Institute of Immunology, University of Münster , Münster , Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.affiliation: Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Wagner
authors.affiliation: Pediatric Immunology, Department of Pediatrics, RWTH Aachen University , Aachen , Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Tenbrock
keywords: CREB; CREM; IL-21; NFAT; SLE; autoimmunity