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 expression via NFATc2 activation. However, CREMα directly binds to cAMP-response element (CRE) half-site within the Il-21 promoter, 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.

Highlights

  • CAMP-responsive element modulator (CREM) is a member of the ATF/CREB type bZip transcription factors family. cAMP activates proteinkinase A that phosphorylates and activates CREB and cAMP-responsive element modulator (CREM)

  • We describe the role of CREMα for the transcriptional activity of the Il-21 promoter

  • Ca2+ is central for IL-21 transcription, since it activates NFAT, which is the most important transcription factor for activation of the IL-21 promoter [23]. Apart from this we found a striking upregulation of Il-21 transcription in CREMα tg T cells by Phorbol12-myristat-13-acetate and ionomycin (P/I) stimulation, which suggest a mechanism independent from the T cell receptor

Read more

Summary

INTRODUCTION

CAMP-responsive element modulator (CREM) is a member of the ATF/CREB type bZip transcription factors family. cAMP activates proteinkinase A that phosphorylates and activates CREB and CREM. The observed effects of CREMα on IL-2 and IL-17a cytokine production in humans are observed in transgenic mice with T cell-specific CREMα overexpression (under control of the cd promoter) [CREMα transgenic (tg)] [7] These mice have decreased IL-2 and increased IL-17a levels and are more prone to develop signs of autoimmunity (including lymphadenopathy and higher autoantibody titers against double-stranded DNA) when an additional genetic deletion of the cd gene (Fas) is present [7, 8]. IL-21 modulates the activity of several cell types that contribute to tissue damage in IBD With this regard, it is not surprising that mice lacking IL-21 are unable to upregulate Th17-associated molecules during experimental gut inflammation and are largely protected against chemically induced colitis [29, 30]. By a comparative analysis of CREMα and wild-type (WT) mice in an experimental colitis model, which is associated with T cellular IL-21 production, we wanted to study the consequences of CREMα-induced cytokine alterations

MATERIALS AND METHODS
RESULTS
DISCUSSION
Full Text
Published version (Free)

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call