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The Bromodomain Protein Inhibitor I-BET151 Suppresses Expression of Inflammatory Genes and Matrix Degrading Enzymes in Rheumatoid Arthritis Synovial Fibroblasts

The Bromodomain Protein Inhibitor I-BET151 Suppresses Expression of Inflammatory Genes and Matrix Degrading Enzymes in Rheumatoid Arthritis Synovial Fibroblasts

Kerstin Klein, Pawel A Kabala, Aleksander M Grabiec, Renate E Gay, Christoph Kolling, Lih-Ling Lin, Steffen Gay, Paul P Tak, Rab K Prinjha, Caroline Ospelt, Kris A Reedquist

Ann Rheum Dis. 2016 Feb;75(2):422-9.

PMID: 25467295

Abstract:

Objective:
To investigate the effects of BET bromodomain protein inhibition on inflammatory activation and functional properties of rheumatoid arthritis synovial fibroblasts (RASF).
Methods:
The expression of the BET bromodomain proteins BRD2, BRD3 and BRD4 was analysed in synovial tissue by immunohistochemistry. RASF were stimulated with tumour necrosis factor (TNF)-α, interleukin (IL)-1β and toll-like receptor (TLR) ligands (Pam3, pIC and lipopolysaccharide (LPS)) in the presence or absence of the BET inhibitor I-BET151, or siRNA targeting BRD2, BRD3 and BRD4. RASF expression of inflammatory mediators, including MMP1, MMP3, IL-6 and IL-8, was measured by q-PCR, q-PCR array and ELISA. Cellular viability, apoptosis, proliferation and chemoattractive properties of RASF were investigated using MTT, cell apoptosis ELISA, BrdU-based proliferation and transwell migration assays.
Results:
BRD2, BRD3 and BRD4 proteins were detected in rheumatoid arthritis (RA) synovial tissue, expressed in both RASF and macrophages. I-BET151 suppressed cytokine and TLR ligand-induced secretion of MMP1, MMP3, IL-6 and IL-8, and mRNA expression of more than 70% of genes induced by TNF-α and IL-1β. Combined silencing of BRD2, BRD3 and BRD4 significantly reduced cytokine and TLR ligand-induced expression of a subset of gene products targeted by I-BET151, including MMP1, CXCL10 and CXCL11. I-BET151 treatment of RASF reduced RASF proliferation, and the chemotactic potential for peripheral blood leucocytes of RASF conditioned medium.
Conclusions:
Inhibition of BET family proteins suppresses the inflammatory, matrix-degrading, proliferative and chemoattractive properties of RASF and suggests a therapeutic potential in the targeting of epigenetic reader proteins in RA.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42415337	Collagenase Inhibitor I			Price

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