CAMP-responsive Element Modulator α (CREMα) Suppresses IL-17F Protein Expression in T Lymphocytes from Patients with Systemic Lupus Erythematosus (SLE)

Christian M Hedrich,Thomas Rauen,Katalin Kis-Toth,Vasileios C Kyttaris,George C Tsokos

doi:10.1074/jbc.m111.323261

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.

Highlights

CREM␣ is increased in systemic lupus erythematosus (SLE) T cells, and it suppresses IL-2, it enhances IL-17A production
T lymphocytes from patients with systemic lupus erythematosus (SLE) display increased expression of transcription factor cAMP-responsive element modulator ␣ (CREM␣), which has been documented to account for aberrant T cell function and contributes to the pathogenesis of SLE
We further demonstrated that CREM␣ is involved in epigenetic remodeling of cytokine genes through histone deacetylase 1 (HDAC1) and DNA methyltransferase 3a (DNMT3a) recruitment to regulatory gene sequences

Summary

Introduction

CREM␣ is increased in SLE T cells, and it suppresses IL-2, it enhances IL-17A production. Results: CREM␣ binds to the IL17F promoter and suppresses its expression in SLE T cells. 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. We demonstrate that CREM␣ 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). Our findings demonstrate extended involvement of CREM␣ 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

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