B cell activating factor-dependent expression of vascular endothelial growth factor in MH7A human synoviocytes stimulated with tumor necrosis factor-α

Abstract

Angiogenesis in rheumatoid arthritis (RA) is one of the histological hallmarks, which is mediated by expression of vascular endothelial growth factor (VEGF) in RA synovium. VEGF expression is enhanced by TNF-α, the main pro-inflammatory cytokine in RA. B cell activating factor (BAFF) which plays a role in maturation and maintenance of B cells is also associated with autoimmune RA. Here, we investigated whether BAFF could regulate VEGF expression in TNF-α-stimulated synovium using MH7A synovial cells that are established by transfection with the SV40 T antigen. Changes in hBAFF and hVEGF were measured by western blotting, RT-PCR and luciferase promoter assay. When MH7A cells were treated with TNF-α, we observed that TNF-α increased the expression of hBAFF and hVEGF. TNF-α also increased transcriptional activity of hBAFF and hVEGF as judged by luciferase promoter assay. Inhibition of hBAFF expression with BAFF-siRNA decreased transcriptional level and activity of hVEGF. In addition, when c-fos expression was inhibited by the transfection of MH7A cells with c-fos-siRNA, data showed that transcriptional level and activity of both hBAFF and hVEGF were attenuated by the activation with TNF-α. Our results demonstrate for the first time that VEGF-mediated angiogenesis in RA could be controlled by TNF-α-induced BAFF expression through c-Fos. Data suggest that TNF-α-induced BAFF expression and BAFF-mediated VEGF expression in synovium may cooperate to maintain the capacity of such cells to protect B cells from apoptosis and the supply of nutrients and oxygen in inflammatory microenvironments.

Synovial cell death is regulated by TNF-α-induced expression of B-cell activating factor through an ERK-dependent increase in hypoxia-inducible factor-1α

“…As HIF-1 α is associated with the pathogenesis of RA 8, 9 and BAFF controls RA angiogenesis, 31 we investigated whether BAFF expression is regulated by HIF-1 α in FLS. We examined hBAFF and HIF-1 α expression levels under normoxic conditions, and MH7A cells were treated with various concentrations of TNF- α for different times (Figure 2).…”

“…27, 29, 30 We reported previously that TNF- α -induced BAFF controls RA angiogenesis by regulating vascular endothelial growth factor (VEGF) expression in synoviocytes. 31 …”

The role of BAFF in the progression of rheumatoid arthritis

“…It has been confirmed that RA-FLS stimulated by IFN-c or TNF-a can induce significant increases in the BAFF mRNA and protein levels [14]. Lee GH and his colleagues showed that the upregulated expression of BAFF could be coupled with VEGF-mediated angiogenesis in FLS [15].…”

“…In contrast, it is upregulated in activated T cells and activated or malignant B cells [13]. The expression of BAFF is upregulated by multiple cytokines, including TNF-a, IFN-c, and TGF-b as well as estrogen [14,15].…”

MicroRNA-663 activates the canonical Wnt signaling through the adenomatous polyposis coli suppression

“…FLS thus enhance immune responses to antigens generated by continual degradation of articular cartilage. Much evidence suggests that FLS promote angiogenesis via expression of SDF-1, fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) [28,29]. FLS have also been suggested to participate in osteoclastogenesis, which is a pivotal mediator of bone erosion in RA.…”