Cho C S, Cho M L, Min S Y, Kim W U, Min D J, Lee S S, Park S H, Choe J, Kim H Y
Department of Medicine, Division of Rheumatology, Center for Rheumatic Diseases in Kangnam St. Mary's Hospital, Seoul, Korea.
J Immunol. 2000 May 15;164(10):5055-61. doi: 10.4049/jimmunol.164.10.5055.
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.
我们测试了CD40激活对类风湿性滑膜成纤维细胞产生血管内皮生长因子（VEGF）的影响。从类风湿性关节炎患者的滑膜组织中制备成纤维样滑膜细胞（FLS），并在转染了CD40配体的（CD40L+）L细胞存在的情况下进行培养。通过ELISA测定培养上清液中的VEGF水平。CD40L+ L细胞对FLS的刺激使VEGF的产生比未刺激的FLS的基础水平增加了4.1倍。来自类风湿性滑液的活化T细胞上的CD40L也上调了FLS中VEGF的产生。吲哚美辛以及针对IL-1β、TNF-α和TGF-β的抗体均未影响CD40L诱导的VEGF产生。用TNF-α、IL-1β和TGF-β刺激FLS分别使VEGF的产生增加了1.6倍、2.0倍和5.2倍，并且对CD40L诱导的VEGF产生具有累加效应。用CD40L+ L细胞的膜刺激FLS也上调了VEGF mRNA的表达。地塞米松完全消除了CD40L诱导的VEGF产生。此外，吡咯烷二硫代氨基甲酸盐部分下调了CD40L诱导的VEGF产生，表明NF-κB途径部分参与了导致VEGF产生的CD40L信号传导。总体而言，这些结果表明滑膜成纤维细胞上的CD40与活化T淋巴细胞上表达的CD40L之间的相互作用可能通过增强VEGF的产生而直接参与类风湿性滑膜炎的新生血管形成。
