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-1beta, TNF-alpha, and TGF-beta did affect CD40L-induced VEGF production. Stimulation of FLS with TNF-alpha, IL-1beta, and TGF-beta 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-kappaB 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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adjuvants, Immunologic / physiology
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Animals
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Arthritis, Rheumatoid / immunology
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CD40 Antigens / immunology*
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CD40 Antigens / metabolism*
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CD40 Ligand
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Cells, Cultured
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Cytokines / pharmacology
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Dexamethasone / pharmacology
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Dinoprostone / biosynthesis
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Endothelial Growth Factors / antagonists & inhibitors
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Endothelial Growth Factors / biosynthesis*
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Endothelial Growth Factors / genetics
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Fibroblasts / drug effects
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Fibroblasts / immunology*
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Fibroblasts / metabolism
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Humans
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Immunosuppressive Agents / pharmacology
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Interleukin-1 / biosynthesis
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L Cells
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Ligands
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Lymphocyte Activation
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Lymphokines / antagonists & inhibitors
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Lymphokines / biosynthesis*
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Lymphokines / genetics
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Membrane Glycoproteins / pharmacology
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Mice
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Pyrrolidines / pharmacology
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RNA, Messenger / biosynthesis
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Synovial Fluid / cytology*
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Synovial Fluid / drug effects
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Synovial Fluid / immunology*
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Synovial Fluid / metabolism
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T-Lymphocyte Subsets / immunology
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Thiocarbamates / pharmacology
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Transforming Growth Factor beta / biosynthesis
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Tumor Necrosis Factor-alpha / biosynthesis
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Up-Regulation / drug effects
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Up-Regulation / immunology*
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
Substances
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Adjuvants, Immunologic
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CD40 Antigens
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Cytokines
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Endothelial Growth Factors
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Immunosuppressive Agents
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Interleukin-1
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Ligands
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Lymphokines
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Membrane Glycoproteins
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Pyrrolidines
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RNA, Messenger
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Thiocarbamates
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Transforming Growth Factor beta
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Tumor Necrosis Factor-alpha
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Vascular Endothelial Growth Factor A
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Vascular Endothelial Growth Factors
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CD40 Ligand
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pyrrolidine dithiocarbamic acid
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Dexamethasone
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Dinoprostone