CD40 Engagement on Synovial Fibroblast Up-Regulates Production of Vascular Endothelial Growth Factor

Abstract

We tested the impact of CD40 engagement on the production of vascular endothelial growth factor (VEGF) from rheumatoid synovial fibroblasts. Fibroblast-like synovial cells (FLS) were prepared from the synovial tissues of rheumatoid arthritis patients and cultured in the presence of CD40 ligand-transfected (CD40L+) L cells. VEGF levels were determined in the culture supernatants by ELISA. Stimulation of FLS by CD40L+ L cells increased the production of VEGF by 4.1-fold over the constitutive levels of unstimulated FLS. The CD40L on activated T cells from rheumatoid synovial fluid also up-regulated VEGF production from FLS. Neither indomethacin nor Abs to IL-1β, TNF-α, and TGF-β did affect CD40L-induced VEGF production. Stimulation of FLS with TNF-α, IL-1β, and TGF-β increased VEGF production by 1.6-, 2.0-, and 5.2-fold, respectively, and displayed an additive effect on the production of VEGF by CD40L. VEGF mRNA expression was also up-regulated by the stimulation of FLS with membranes from the CD40L+ L cells. Dexamethasone completely abrogated CD40L-induced VEGF production. In addition, pyrrolidine dithiocarbamate partially down-regulated CD40L-induced VEGF production, showing that the NF-κB pathway was partly involved in the signaling of CD40L leading to VEGF production. Collectively, these results suggest that the interaction between CD40 on synovial fibroblasts and CD40L expressed on activated T lymphocytes may be directly involved in the neovascularization in rheumatoid synovitis by enhancing the production of VEGF.

CD40-induced transcriptional activation of vascular endothelial growth factor involves a 68-bp region of the promoter containing a CpG island

“…Autoradiographs are representative of 6 independent experiments. promote activation responses including the expression of the angiogenesis factor VEGF (12,41,53,62). In this study, we identified a CD40-responsive element for VEGF expression in EC and we show that it resides within a 68-bp region of the VEGF promoter.…”

Amplification of the synovial inflammatory response through activation of mitogen‐activated protein kinases and nuclear factor κB using ligation of CD40 on CD14+ synovial cells from patients with rheumatoid arthritis

“…Other investigators have also demonstrated that CD68ϩ synovial macrophage lineage cells as well as fibroblast-like synoviocytes (FLS) express CD40 (8,9). The ligation of CD40 augments the production of IL-12 in synovial cells and synovial fluid macrophages from RA patients (10,11) and enhances the expression of CD54, CD106, IL-6 (12), stromal cell-derived factor 1 (13), and vascular endothelial cell growth factor (14). In vivo, treatment with a monoclonal antibody (mAb) against CD154 prevents the development of type II collagen-induced arthritis in mice (15).…”

Autocrine VEGF mediates the antiapoptotic effect of CD154 on CLL cells

“…17 Stimulation of CD40 on endothelial cells, monocytes, fibroblasts and multiple myeloma cells upregulates production of VEGF by these cells. [18][19][20] Furthermore, neutralisation of autocrine VEGF by anti-VEGF antibody (Ab) completely abolished the mitogenic effect of CD154 on endothelial cells. 18 In CLL cells, ligation of CD40 by CD154 is known to inhibit spontaneous and drug-induced cell death.…”