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Potent anti-inflammatory effects of the narrow spectrum kinase inhibitor RV1088
on rheumatoid arthritis synovial membrane cells
#MMPMID25891413
To WS
; Aungier SR
; Cartwright AJ
; Ito K
; Midwood KS
Br J Pharmacol
2015[Aug]; 172
(15
): 3805-16
PMID25891413
show ga
BACKGROUND AND PURPOSE: To investigate whether a narrow spectrum kinase inhibitor
RV1088, which simultaneously targets specific MAPKs, Src and spleen tyrosine
kinase (Syk), is more effective at inhibiting inflammatory signalling in
rheumatoid arthritis (RA) than single kinase inhibitors (SKIs). EXPERIMENTAL
APPROACH: elisas were used to determine the efficacy of RV1088, clinically
relevant SKIs and the pharmaceutical Humira on pro-inflammatory cytokine
production by activated RA synovial fibroblasts, primary human monocytes and
macrophages, as well as spontaneous cytokine synthesis by synovial membrane cells
from RA patients. In human macrophages, RNAi knockdown of individual kinases was
used to reveal the effect of inhibition of kinase expression on cytokine
synthesis. KEY RESULTS: RV1088 reduced TNF-?, IL-6 and IL-8 production in all
individual activated cell types with low, nM, IC50 s. SKIs, and combinations of
SKIs, were significantly less effective than RV1088. RNAi of specific kinases in
macrophages also caused only modest inhibition of pro-inflammatory cytokine
production. RV1088 was also significantly more effective at inhibiting IL-6 and
IL-8 production by monocytes and RA synovial fibroblasts compared with Humira.
Finally, RV1088 was the only inhibitor that was effective in reducing TNF-?, IL-6
and IL-8 synthesis in RA synovial membrane cells with low nM IC50 s. CONCLUSIONS
AND IMPLICATIONS: This study demonstrates potent anti-inflammatory effect of
RV1088, highlighting that distinct signalling pathways drive TNF-?, IL-6 and IL-8
production in the different cell types found in RA joints. As such, targeting
numerous signalling pathways simultaneously using RV1088 could offer a more
powerful method of reducing inflammation in RA than targeting individual kinases.
free
free
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