IL-6/sIL-6R trans-signalling, but not TNF-α induced angiogenesis in a HUVEC and synovial cell co-culture system
IL-6/sIL-6R trans-signalling, but not TNF-α induced angiogenesis in a HUVEC and synovial cell co-culture system
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DOI：
10.1007/s00296-009-0885-8
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发表时间：
2009-10-01
影响因子：
4
通讯作者：
Mihara, Masahiko
中科院分区：
文献类型：
--
作者：
Hashizume, Misato;Hayakawa, Naohiko;Mihara, Masahiko
滑膜血管生成是类风湿关节炎患者的特征。我们研究了IL-6或TNF-α是否在RA患者成纤维细胞样滑膜细胞（RA-FLS）和人脐静脉内皮细胞（HUVEC）的共培养系统中诱导小管形成。观察IL-6和TNF-α对RA-FLS和HUVEC中血管生成因子表达及HUVEC增殖的影响。IL-6 + sIL-6 R诱导肾小管形成，而单独IL-6则不诱导。IL-6/sIL-6 R诱导的肾小管形成被抗IL-6 R或抗VEGF抗体完全抑制。TNF-α不诱导小管形成。相反，与对照相比，其减少了CD 31阳性面积。IL-6 + sIL-6 R可增加RA-FLS中VEGF的产生，而单独IL-6则无此作用。抗IL-6 R抗体抑制IL-6/sIL-6 R诱导的VEGF产生，但不抑制自发的VEGF产生。相反，TNF-α不诱导RA-FLS和HUVEC产生VEGF。IL-6 + sIL-6 R刺激RA-FLS强烈诱导VEGF的mRNA表达，但不诱导其他血管生成因子如EGF、bFGF、TGF-β、IL-1、TNF-α和IL-8的mRNA表达。IL-6和IL-6/sIL-6 R均不促进HUVEC增殖，而TNF-α显著抑制VEGF诱导的HUVEC增殖。总之，IL-6/sIL-6 R复合物通过从RA-FLS产生VEGF而显示血管生成活性，但TNF-α在我们的实验系统中是抗血管生成的。
Angiogenesis in synovia is a characteristic of RA patients. We examined whether IL-6 or TNF-alpha induce tubule formation in a co-culture system of fibroblast-like synovial cells from RA patients (RA-FLS) and human umbilical vein endothelial cells (HUVEC). The effects of IL-6 and TNF-alpha on the expression of angiogenic factors in RA-FLS and HUVEC, and the proliferation of HUVEC were also studied. IL-6 + sIL-6R induced tubule formation, whereas IL-6 alone did not. IL-6/sIL-6R-induced tubule formation was completely suppressed by the addition of either anti-IL-6R or anti-VEGF antibody. TNF-alpha did not induce tubule formation. On the contrary, it decreased CD31-positive area compared with the control. IL-6 + sIL-6R augmented VEGF production in RA-FLS, whereas IL-6 alone did not. Anti-IL-6R antibody suppressed IL-6/sIL-6R-induced VEGF production, but not spontaneous VEGF production. In contrast, TNF-alpha did not induce VEGF production from RA-FLS and HUVEC. IL-6 + sIL-6R stimulation of RA-FLS strongly induced mRNA expression of VEGF, but not of other angiogenic factors, such as EGF, bFGF, TGF-beta, IL-1, TNF-alpha and IL-8. Neither IL-6 nor IL-6/sIL-6R promoted HUVEC proliferation, whereas TNF-alpha significantly inhibited VEGF-induced HUVEC proliferation. In conclusion, IL-6/sIL-6R complex showed angiogenic activity via the production of VEGF from RA-FLS, but TNF-alpha was anti-angiogenic in our experimental system.