CD147分子通过VEGF促进类风湿关节炎滑膜组织中的血管新生

CD147 stimulates the angiogenesis in rheumatoid synovium via the activation of vascular endothelial growth factor

目的观察类风湿关节炎(RA)滑膜组织中CD147表达强度与血管内皮生长因子(VEGF)表达水平间的相关性,并探讨成纤维样滑膜细胞(FLS)表面CD147的水平变化对VEGF表达的影响。方法收集15例RA患者滑膜,以4例骨关节炎(OA)患者滑膜作对照,采用免疫组织化学SP染色方法检测滑膜组织中CD147和VEGF的表达;体外原代培养FLS细胞,分别加入CD147抗体,PI3K通路阻断剂,MAPK通路的ERK1/2、P38及JNK阻断剂等作用FLS细胞,ELISA检测细胞培养上清中VEGF的表达水平。结果与4例OA滑膜组织CD147和VEGF表达相比,15例RA滑膜组织中均有CD147、VEGF均高表达。其中,表达CD147的细胞主要为成纤维样滑膜细胞、单核-巨噬细胞和淋巴细胞;表达VEGF的细胞主要为成纤维样滑膜细胞、微血管周围成纤维样细胞及血管平滑肌细胞。滑膜组织中CD147和VEGF的表达强度间具有统计学意义。ELISA结果显示,在使用LY294002或抗HAb18GmAb阻断CD147表达后,VEGF的表达量显著下降(P<0.05);而MAPK阻断剂(PD98059、SP600125和SB203580)等对VEGF表达水平无统计学意义(P>0.05)。结论CD147经PI3K-Akt信号通路在RA滑膜组织中上调VEGF促进血管新生。提示CD147在RA血管新生和血管翳形成中有重要意义。

AIM： To observe the correlation between vascular endothelial growth factor（VEGF） and CD147 expressed in the rheumatoid synovium and to investigate the effect of CD147 of cultured rheumatoid fibroblast-like synoviocytes （FLS） on the production of VEGF, METHODS： The presence of CD147 and VEGF in the rheumatoid synovium derived from 15 patients with RA and 4 patients with osteoarthritis（OA） was detected by streptavidin/peroxidase （SP） immunostaining. FLS were cultured by enzymatic digestion of synovial tissues and incubated in 24-well plates. Then different concentration of LY294002, PD98059, SP600125, SB203580 and HAb18G mAb was added to each well. VEGF in the culture supernatant was measured by sandwich ELISA. RESULTS： CD147 and VEGF in synovium from 15 patients with RA showed high expression, while CD147 and VEGF in synovium from 4 patients with OA showed low expression. Macrophages, fibroblast-like synovial cells and lymphocytes were demonstrated to express CD147 while synovial lining cells, fibroblasts surrounding microvessels and vascular smooth muscle cells were demonstrated to express VEGF. Statistic analysis indicates that VEGF production was correlated with the levels of CD147 expression. VEGF production was suppressed when CD147 expression was inhibited by LY294002 or HAblSG mAb. CONCLUSION： CD147 can regulate the angiogenesis in rheumatoid arthritis by VEGF. The low levels of CD147 expressed by FLS cells decrease the production of VEGF via the PI3K-Akt signaling pathway. These findings further highlight the importance of CD147 in pannus formation and angiogenesis.