期刊
EXPERIMENTAL EYE RESEARCH
卷 84, 期 5, 页码 812-822出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.exer.2006.12.016
关键词
human retinal pigment epithelium; TGF-beta 2; VEGF; bFGF; TNF-alpha; synergy
资金
- NEI NIH HHS [P30 EY007003, P30 EY007003-20, F31 EY007003, EY-09441, EY007003, R01 EY009441, R01 EY009441-12] Funding Source: Medline
VEGF secretion by the human retinal pigment epithelium (hRPE) plays an important role in retinal and choroidal neovascularization. In this study, transforming growth factor-beta 2 (TGF-beta 2)-induced vascular endothelial growth factor (VEGF) gene expression was investigated in hRPE cells. Treatment of hRPE cells with TGF-beta 2 for 24 and 48 h as compared to 8 h resulted in markedly increased VEGF secretion by fivefold and nine-fold, respectively. Induced VEGF mRNA peaked within 3 h of stimulation and remained above the basal at 36 h. Stimulation of VEGF expression by TGF-beta 2 was blocked by cycloheximide, suggesting that de novo protein synthesis is required. Induced VEGF production was strongly inhibited by anti-in flammatoryagents, dexamethasone and cyclosporin A. Despite of the weak stimulation of VEGF expression by TNF-alpha or bFGF alone, co-administration of either of these two cytokines synergized the effect of TGF-beta 2 on VEGF mRNA expression and protein production. Quantitative RT-PCR revealed that the synergy was predominantly at the level of VEGF transcription. Moreover, TGF-beta 2-induced RPE VEGF secretion was significantly reduced by inhibitors of mitogen-activated protein (MAP) kinase (MEK) (UO126), p38 (SB202190), c-Jun NH2-terminal kinase (JNK), Sp600125, protein tyrosine kinase (PTK) (Genistein), and pbosphatidylinositol 3-kinase (PI3K) (Ly294002). Induced VEGF expression was completely abrogated by inhibitors of protein kinase C (PKC) (Ro318220), nuclear factor-kappa B (NF-kappa B) [caffeic acid phenethyl ester (CAPE)], and reactive oxygen species (ROS) [N-acetyl-cysteine (Nac) and diphenyleneiodonium (DPI)]. These results suggest that MEK, p38, JNK, PI3K, and NF-kappa B as well as multiple essential signaling intermediates, including PKC, PTK and ROS, are involved in hRPE VEGF up regulation by TGF-beta 2. (C) 2006 Elsevier Ltd. All rights reserved.
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