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TNF-α induces expression of the circadian clock gene Bmal1 via dual calcium-dependent pathways in rheumatoid synovial cells
- Source :
- Biochemical and Biophysical Research Communications. 495(2):1675-1680
- Publication Year :
- 2018
- Publisher :
- Elsevier, 2018.
-
Abstract
- Tumor necrosis factor (TNF)-α is responsible for expressions of several clock genes and affects joint symptoms of rheumatoid arthritis (RA) with diurnal fluctuation. We tried to determine the mechanism involved in over-expression of Bmal1, induced by TNF-α, in primary cultured rheumatoid synovial cells. Cells were incubated with intra-cellular Ca2+ chelator BAPTA-AM, calcineurin inhibitor FK506 and p300/CBP (CREB binding protein) inhibitor C646, respectively, or transfected with p300 and CBP small interfering RNA (siRNA) before stimulation with TNF-α. Oscillation phase and amplitude of Bmal1, transcriptional activator Rorα, transcriptional repressor Rev-erbα, and histone acetyltransferases (p300 and Cbp) were evaluated by quantitative real-time PCR. As results, TNF-α did not influence the oscillation phase of Rev-erbα, while enhanced those of Rorα, resulting in over-expression of Bmal1. When Ca2+ influx was inhibited by BAPTA-AM, TNF-α-mediated up-regulation of Rorα was cancelled, however, that of Bmal1 was still apparent. When we further explored another pathway between TNF-α and Bmal1, TNF-α suppressed the expression of Rev-erbα in the absence of Ca2+ influx, as well as those of p300 and Cbp genes. Finally, actions of TNF-α, in increasing Bmal1/Rorα and decreasing Rev-erbα, were cancelled by C646 treatment or silencing of both p300 and Cbp. In conclusion, we determined a novel role of TNF-α in inducing Bmal1 via dual calcium dependent pathways; Rorα was up-regulated in the presence of Ca2+ influx and Rev-erbα was down-regulated in the absence of that. Results proposed that inhibition of p300/CBP could be new therapeutic targets for RA.
- Subjects :
- 0301 basic medicine
Small interfering RNA
endocrine system
Biophysics
Gene Expression
Stimulation
Calcium signal
Biochemistry
Benzoates
Arthritis, Rheumatoid
03 medical and health sciences
Circadian Clocks
Gene silencing
Humans
Calcium Signaling
RNA, Messenger
CREB-binding protein
Pyrazolones
RNA, Small Interfering
Rheumatoid arthritis
Molecular Biology
Egtazic Acid
Cells, Cultured
Nitrobenzenes
Calcium Chelating Agents
biology
Synovial
Chemistry
Tumor Necrosis Factor-alpha
Circadian rhythm
Synovial Membrane
ARNTL Transcription Factors
Nuclear Receptor Subfamily 1, Group F, Member 1
Cell Biology
Transfection
Fibroblasts
CREB-Binding Protein
Cell biology
CLOCK
Calcineurin
030104 developmental biology
Nuclear Receptor Subfamily 1, Group D, Member 1
Tumor necrosis factor-alpha (TNF-α)
biology.protein
Pyrazoles
Tumor necrosis factor alpha
E1A-Associated p300 Protein
Subjects
Details
- Language :
- English
- ISSN :
- 0006291X
- Volume :
- 495
- Issue :
- 2
- Database :
- OpenAIRE
- Journal :
- Biochemical and Biophysical Research Communications
- Accession number :
- edsair.doi.dedup.....38a170b589b666074c2812ca4cef4058