Hypoxia augments cytokine (transforming growth factor-beta (TGF-β) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts

Abstract

SUMMARYVascular endothelial growth factor (VEGF) is abundant in synovium and synovial fluids, where it probably contributes to vascular permeability and angiogenesis in arthritic joints. To investigate the probable sources of VEGF in synovium, we compared the ability of several cytokines (TGF-b, plateletderived growth factor (PDGF), IL-1, tumour necrosis factor (TNF), basic fibroblast growth factor (bFGF) that are associated with arthritis and angiogenesis, to stimulate secretion of VEGF protein by human synovial fibroblasts. TGF-b was the strongest inducer of VEGF secretion; six times more VEGF was secreted when cells were stimulated by TGF-b than when stimulated by PDGF or IL-1 for 24 h. TNF-a and bFGF did not stimulate any secretion of VEGF. The stimulatory effects of TGF-b and IL-1 on VEGF secretion were additive. Hypoxic culture alone also stimulated VEGF secretion, but more importantly, hypoxic culture conditions doubled the rate of VEGF secretion stimulated by the cytokines TGF-b and IL-1. When dermal and synovial fibroblasts were stimulated identically by hypoxia and cytokines (TGF-b and IL-1), synovial fibroblasts secreted four times more VEGF than did dermal fibroblasts. Thus in rheumatoid arthritis, the capacity of synovial fibroblasts in the hypoxic environment to secrete large amounts of VEGF in response to cytokines such as TGF-b probably contributes significantly to angiogenesis in the synovium.

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

“…In the present study, IL-1␤, TNF-␣, and TGF-␤ increased the secretion of VEGF by factors of 2.0, 1.6, and 5.2, respectively, compared with the control, which is consistent with the results of previous studies (12,13,15,41). Notably, the combined effect of CD40L ϩ L cells with these cytokines was additive and not synergistic.…”

“…VEGF is also highly expressed in the inflamed synovium of RA, where it is produced by synovial fibroblasts and activated macrophages (9,11). An important stimulus for VEGF release is hypoxia, which up-regulates VEGF protein and mRNA expression in rheumatoid synovial cells (12)(13)(14). In addition, inflammatory mediators which play an important role in the pathogenesis of RA, including PG (15), IL-1, IL-6 (15,16), and TGF-␤ (13,17), have been described to induce VEGF.…”

“…TGF-␤ is also known to be a potent inducer of VEGF in synovial cells and some other cells (13,17). Thus, a series of inhibition studies using Abs to IL-1␤, TNF-␣, and TGF-␤, and PGE 2 synthesis inhibitor was conducted in an effort to investigate whether VEGF production from FLS was mediated through endogenous production of these substances.…”

Complexity of tumor vasculature in clear cell renal cell carcinoma

“…Theoretically, tumor cells with aberrant VHL genes might not produce more VEGF in response to the sudden blood deprivation during surgery. However, VEGF-A can also be produced by macrophages, fibroblasts, endothelial cells, and other cell types, [56][57][58] which are normally able to respond to hypoxic conditions.…”

Interleukin‐8, Interleukin‐10, Intercellular Adhesion Molecule‐1 and Vascular Cell Adhesion Molecule‐1 Expression Levels are Higher in Synovial Tissue from Patients with Rheumatoid Arthritis than in Osteoarthritis

“…Thus, T-cell and neutrophil chemotaxis, a crucial process for leucocyte accumulation, is predominantly induced by interleukin (IL)-8 [6][7][8][9][10]. Other cytokines, such as IL-1, IL-6, tumour necrosis factor-␣ (TNF-␣), granulocyte and monocyte colony-stimulating factor (GM-CSF), transforming growth factor-␤ (TGF-␤) and IL-10, have also been detected in the RA joint [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Overexpression of IL-1␣, IL-1␤, IL-6, TNF-␣, GM-CSF and epidermal growth factor (EGF) has been described in OA synovium [4,[24][25][26].…”