Artikel
The transcription factor CREMalpha regulates inflammatory T cell subsets in juvenile idiopathic arthritis
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Veröffentlicht: | 12. September 2014 |
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Gliederung
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Background: The cAMP response element (CRE) modulator (CREM)α binds to promoters of genes with CREs and regulates transcription via a chromatin-dependent mechanism. CREMα is important for the T cell pathophysiology of SLE by suppression of IL-2 and CD3ζ but enhancement of IL-17 transcription. Juvenile idiopathic arthritis (JIA) is an autoimmune disease of unknown origin. Th17 cells have a pathogenic role in arthritis and are not controlled by local FoxP3+ regulatory T cells (Tregs). Pathogenic T cells in the inflamed joints of JIA patients have enhanced expression of IL-17, IFN-γ and CD161. CD161+ CD4+ cells also contain FoxP3+ cells that produce proinflammatory cytokines. A higher frequency of CD161 Tregs appears to associate with more severe disease in JIA, a fact which might contribute to the failure by Treg to suppress ongoing inflammation.
Methods: Surface cell markers and cytokines were analysed by flow cytometry. mRNA levels were measured by quantitative RT-PCR. si RNA was transfected with electroporation
Results: The aim of this study was to evaluate the role of CREM expressing T cells in juvenile idiopathic arthritis. We observed enhanced expression of CREM in synovial fluid T cells from JIA patients. Enhanced expression of CREM was also induced after ex vivo culture of PBMCs from healthy donors with synovial fluid from JIA patients. We furthermore found enhanced expression of CREM in CD4+CD161+ and in CD4+FoxP3+CD161+ cells, which are known producers of inflammatory cytokines. Vice versa Helios+FoxP3+ cells, which are supposed to be stable Tregs and do not express inflammatory cytokines, showed lower levels of CREM expression. Incubation with SF induced the expression of IFN-γ, IL-17 and FoxP3 in T cells, which could be reserved by transfection of CREM siRNA. Within the FoxP3+ population, CREMsiRNA reduced CD161+FoxP3+ cells but hardly affected Helios+FoxP3+ cells. Interestingly in in vitro assays Enbrel as well as Anakinra, which are both used to treat arthritis, downregulated CREM expression as well as expression of inflammatory cytokines in T cells.
Conclusion: We thus suggest that the overexpression of CREMalpha in T cells contributes to T cell pathophysiology in JIA by regulating percentages of inflammatory CD4+ IL-17+ producing cells, as well as inflammatory CD161+FoxP3+ cells.