Differentially Expressed in Chondrocytes 2 (DEC2) Increases the Expression of IL-1 beta and Is Abundantly Present in Synovial Membrane in Rheumatoid Arthritis

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Olkkonen , J , Kouri , V-P , Hynninen , J , Konttinen , Y T & Mandelin , J 2015 , ' Differentially Expressed in Chondrocytes 2 (DEC2) Increases the Expression of IL-1 beta and Is Abundantly Present in Synovial Membrane in Rheumatoid Arthritis ' , PLoS One , vol. 10 , no. 12 , 0145279 . https://doi.org/10.1371/journal.pone.0145279

Title: Differentially Expressed in Chondrocytes 2 (DEC2) Increases the Expression of IL-1 beta and Is Abundantly Present in Synovial Membrane in Rheumatoid Arthritis
Author: Olkkonen, Juri; Kouri, Vesa-Petteri; Hynninen, Joel; Konttinen, Yrjo T.; Mandelin, Jami
Contributor: University of Helsinki, Clinicum
University of Helsinki, Clinicum
University of Helsinki, Clinicum
University of Helsinki, Clinicum
Date: 2015-12-28
Language: eng
Number of pages: 13
Belongs to series: PLoS One
ISSN: 1932-6203
URI: http://hdl.handle.net/10138/160582
Abstract: Objective Patients with rheumatoid arthritis (RA) have altered circadian rhythm of circulating serum cortisol, melatonin and IL-6, as well as disturbance in the expression of clock genes ARNTL2 and NPAS2. In humans, TNF alpha increases the expression ARNTL2 and NPAS2 but paradoxically suppresses clock output genes DPB and PER3. Our objective was to investigate the expression of direct clock suppressors DEC1 and DEC2 (BHLHE 40 and 41 proteins) in response to TNF alpha and investigate their role during inflammation. Methods Cultured primary fibroblasts were stimulated with TNF alpha. Effects on DEC2 were studied using RT-qPCR and immunofluorescence staining. The role of NF-kappa B in DEC2 increase was analyzed using IKK-2 specific inhibitor IMD-0354. Cloned DEC2 was transfected into HEK293 cells to study its effects on gene expression. Transfections into primary human fibroblasts were used to confirm the results. The presence of DEC2 was analyzed in (RA) and osteoarthritis (OA) synovial membranes by immunohistochemistry. Results TNF alpha increased DEC2 mRNA and DEC2 was mainly detected at nuclei after the stimulus. The effects of TNF alpha on DEC2 expression were mediated via NF-kappa B. Overexpression, siRNA and promoter activity studies disclosed that DEC2 directly regulates IL-1 beta, in both HEK293 cells and primary human fibroblasts. DEC2 was increased in synovial membrane in RA compared to OA. Conclusion Not only ARNTL2 and NPAS2 but also DEC2 is regulated by TNF alpha in human fibroblasts. NF-kappa B mediates the effect on DEC2, which upregulates IL-1 beta. Circadian clock has a direct effect on inflammation in human fibroblasts.
Subject: NECROSIS-FACTOR-ALPHA
CIRCADIAN-RHYTHMS
TNF-ALPHA
TRANSCRIPTION
CLOCK
LOOP
FIBROBLASTS
CYTOKINES
FATIGUE
BIOLOGY
3121 General medicine, internal medicine and other clinical medicine
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