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J Biol Chem. 2012 Feb 10;287(7):4715-25. doi: 10.1074/jbc.M111.323261. Epub 2011 Dec 19.

cAMP-responsive element modulator α (CREMα) suppresses IL-17F protein expression in T lymphocytes from patients with systemic lupus erythematosus (SLE).

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1
Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA. chedrich@bidmc.harvard.edu

Abstract

The proinflammatory cytokines IL-17A and IL-17F are primarily produced by Th17 lymphocytes. Both are involved in host defense mechanisms against bacterial and fungal pathogens and contribute to the development of various autoimmune diseases. T lymphocytes from patients with systemic lupus erythematosus (SLE) display increased expression of transcription factor cAMP-responsive element modulator α (CREMα), which has been documented to account for aberrant T cell function and contributes to the pathogenesis of SLE. Here, we provide evidence that IL-17F expression is reduced in SLE T cells. We demonstrate that CREMα binds to a yet unidentified CRE site within the proximal promoter. This results in reduced IL-17F expression in SLE T lymphocytes and is independent of activating epigenetic patterns (increased histone H3 Lys-18 acetylation, reduced histone H3 Lys-27 trimethylation, and CpG-DNA demethylation). Forced CREMα expression in human T lymphocytes results in reduced IL-17F expression. Our findings demonstrate extended involvement of CREMα in cytokine dysregulation in SLE by contributing to a disrupted balance between IL-17A and IL-17F. An increased IL-17A/IL-17F ratio may aggravate the proinflammatory phenotype of SLE.

PMID:
22184122
PMCID:
PMC3281648
DOI:
10.1074/jbc.M111.323261
[Indexed for MEDLINE]
Free PMC Article
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