Largazole, a class I histone deacetylase inhibitor, enhances TNF-α-induced ICAM-1 and VCAM-1 expression in rheumatoid arthritis synovial fibroblasts

Abstract

In the present study, we evaluated the effect of largazole (LAR), a marine-derived class I HDAC inhibitor, on tumor necrosis factor-α (TNF-α)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and matrix metalloproteinase-2 (MMP-2) activity. LAR (1-5 μM) had no adverse effect on the viability of RA synovial fibroblasts. Among the different class I HDACs screened, LAR (1-5 μM) inhibited the constitutive expression of HDAC1 (0-30%). Surprisingly, LAR increased class II HDAC [HDAC6] by ~220% with a concomitant decrease in HDAC5 [30-58%] expression in RA synovial fibroblasts. SAHA (5 μM), a pan-HDAC inhibitor, also induced HDAC6 expression in RA synovial fibroblasts. Pretreatment of RA synovial fibroblasts with LAR further enhanced TNF-α-induced ICAM-1 and VCAM-1 expression. However, LAR inhibited TNF-α-induced MMP-2 activity in RA synovial fibroblasts by 35% when compared to the TNF-α-treated group. Further, the addition of HDAC6 specific inhibitor Tubastatin A with LAR suppressed TNF-α+LAR-induced ICAM-1 and VCAM-1 expression and completely blocked MMP-2 activity, suggesting a role of HDAC6 in LAR-induced ICAM-1 and VCAM-1 expression. LAR also enhanced TNF-α-induced phospho-p38 and phospho-AKT expression, but inhibited the expression of phospho-JNK and nuclear translocation of NF-κBp65 in RA synovial fibroblasts. These results suggest that LAR activates p38 and Akt pathways and influences class II HDACs, in particular HDAC6, to enhance some of the detrimental effects of TNF-α in RA synovial fibroblasts. Understanding the exact role of different HDAC isoenzymes in RA pathogenesis is extremely important in order to develop highly effective HDAC inhibitors for the treatment of RA.

Epigenetics in rheumatoid arthritis

“…Furthermore, the authors showed that LAR modulated expression levels of HDAC1, HDAC5 and HDAC6 and indicated a role of HDAC6 in the LAR-induced changes of ICAM-1 and VCAM-1 expression levels. These results again point to the need for understanding the exact role of different HDAC enzymes in the RA pathogenesis in order to develop highly effective HDAC inhibitors for the treatment of RA [29]. Class I HDAC and HDAC6…”

“…Different HDAC inhibitors (Table 1), which mostly target several members of HDAC, were described to have beneficial effects in vitro and in vivo in RA [17,[25][26][27][28][29][30][31]. However, many of the observed effects of HDAC inhibitors were shown to be chromatin-independent and nonepigenetic (reviewed in [17]).…”

“…However, many of the observed effects of HDAC inhibitors were shown to be chromatin-independent and nonepigenetic (reviewed in [17]). Further studies [29][30][31] (Table 1) have been published within the last 2 years using new and even more potent HDAC inhibitors. Ahmed et al [29] showed that Largazole (LAR), a marine-derived class I HDAC inhibitor, suppressed the TNFa-induced expression of intracellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in RASF, whereas the TNFa-induced MMP2 activity was reduced.…”

“…Further studies [29][30][31] (Table 1) have been published within the last 2 years using new and even more potent HDAC inhibitors. Ahmed et al [29] showed that Largazole (LAR), a marine-derived class I HDAC inhibitor, suppressed the TNFa-induced expression of intracellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) in RASF, whereas the TNFa-induced MMP2 activity was reduced. Furthermore, the authors showed that LAR modulated expression levels of HDAC1, HDAC5 and HDAC6 and indicated a role of HDAC6 in the LAR-induced changes of ICAM-1 and VCAM-1 expression levels.…”

Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

“…Both are implicated in RA pathology through their angiogenic and proliferative effects in inflamed synovium [44][45][46][47]. The infiltration and retention of inflammatory cells in RA synovium is facilitated by upregulation of VCAM-1 on endothelial cells and synovial fibroblasts in this tissue [48]. VCAM-1 was reduced in DTHA paws following anti-C5aR treatment, and as C5aR is expressed on endothelial cells and synovial fibroblasts [7] this reduction in VCAM-1 could represent a direct effect of anti-C5aR treatment on these cells.…”