title: cAMP-responsive element modulator α (CREMα) suppresses IL-17F protein expression in T lymphocytes from patients with systemic lupus erythematosus (SLE).
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.
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA. chedrich@bidmc.harvard.edu
authors.forename: Christian M
authors.initials: CM
authors.lastname: Hedrich
authors.forename: Thomas
authors.initials: T
authors.lastname: Rauen
authors.forename: Katalin
authors.initials: K
authors.lastname: Kis-Toth
authors.forename: Vasileios C
authors.initials: VC
authors.lastname: Kyttaris
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000107:Acetylation; D000328:Adult; D018899:CpG Islands / Q000276:immunology; D051786:Cyclic AMP Response Element Modulator / Q000276:immunology / Q000378:metabolism*; D044127:Epigenesis, Genetic; D005260:Female; D006657:Histones / Q000276:immunology / Q000378:metabolism; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D019169:Jurkat Cells; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008745:Methylation; D008875:Middle Aged; D020218:Response Elements; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: C497410:CREM protein, human; D006657:Histones; C508717:IL17A protein, human; C440021:IL17F protein, human; D020381:Interleukin-17; D051786:Cyclic AMP Response Element Modulator