PDF(Pubmed)
Abstract：
Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin\' s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S.
摘要：
血管生成是类风湿性关节炎(RA)进展的关键。托法替尼的作用，用于RA治疗的JAK-STAT抑制剂，RA中的血管生成尚不清楚。我们,因此,评估了用托法替尼治疗的成纤维细胞(HT1080)和单核细胞(U937)细胞系的两个人类共培养系统以及托法替尼治疗6个月前后的RA患者血清样本中的血管生成因子水平.托法替尼降低CD147水平，基质金属蛋白酶-9(MMP-9)活性,和血管生成潜力，但增加内皮抑素水平和分泌的蛋白酶体20S活性。体外，托法替尼没有改变CD147mRNA,但miR-146a-5p表达增加,STAT3磷酸化降低.我们最近表明CD147调节MMP-9和分泌的蛋白酶体20S将胶原XVIIIA切割成内皮抑素的能力。我们在这里显示，托法替尼增强的内皮抑素水平是由CD147介导的，如CD147-siRNA或抗CD147抗体阻断的蛋白酶体20S活性。CD147与不同疾病严重程度评分之间的相关性支持这一作用。最后,托法替尼通过抑制组织蛋白酶S活性减少内皮抑素的降解,重组组织蛋白酶S在这两个系统中逆转了这一降解.因此，托法替尼通过减少促血管生成因子和增强抗血管生成因子内皮抑素的双重作用来抑制血管生成，该双重作用部分通过CD147和部分通过组织蛋白酶介导。
