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.
Klein K, Kabala PA, Grabiec AM, Gay RE, Kolling C, Lin LL, Gay S, Tak PP, Prinjha RK, Ospelt C, Reedquist KA.
Members of the bromodomain and extra-terminal (BET) protein family (BRD2, BRD3, BRD4, BRDT) are readers of the ε-N-acetylation of lysine residues on histone tails, an epigenetic modification that is associated with an open chromatin architecture and transcriptional activation. BRD2, BRD3 and BRD4 proteins are expressed in synovial fibroblasts and macrophages, the two joint-resident cell types in the synovium. The BET bromodomain inhibitor I-BET151 suppressed the cytokine and Toll-like receptor ligand-induced secretion of the matrix metalloproteinases MMP1, MMP3, as well as the cytokines 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 in synovial fibroblasts that mimicked the inhibitor treatment 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 rheumatoid arthritis synovial fibroblasts reduced their proliferation and the chemotactic potential for peripheral blood leucocytes.
Key idea/result:
Our data on effects of BET bromodomain inhibition on inflammatory activation and functional properties of rheumatoid arthritis synovial fibroblasts suggest a therapeutic potential in targeting of epigenetic reader proteins in RA.
Author:
Kerstin Klein is a senoir postdoctoral scientist at the Centre of Experimental Rheumatology, University Hospital Zurich since 2010. Her major scientific interest is the the role of epigenetic mechanisms in rheumatoid arthritis and the potential of epigenetic enzymes as future therapeutic targets.
Key words:
- Synovial fibroblasts
- Arthritis
- Inflammation
- bromodomain
