Circulating chromogranin A reveals extra-articular involvement in patients with rheumatoid arthritis and curbs TNF-α-elicited endothelial activation
Circulating chromogranin A reveals extra-articular involvement in patients with rheumatoid arthritis and curbs TNF-α-elicited endothelial activation
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DOI：
10.1189/jlb.0608358
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发表时间：
2009-01-01
影响因子：
5.5
通讯作者：
Manfredi, Angelo A.
中科院分区：
文献类型：
--
作者：
Di Comite, Gabriele;Rossi, Carlo M.;Manfredi, Angelo A.
TNF-α在类风湿性关节炎（RA）的自然病程中起着重要作用，RA是一种以内皮活化和滑膜受累伴骨侵蚀为特征的全身性疾病。神经内分泌信号也有助于RA，但其作用知之甚少。我们测量了104例RA患者和相同数量的性别和年龄匹配的健康对照组的嗜铬粒蛋白A（CgA）的血液水平，CgA是一种将神经内分泌系统与TNF-α介导的血管炎症联系起来的候选标记物。CgA水平在RA患者中显著较高，并随时间保持稳定。高水平的CgA与严重的关节外表现显著相关，即肺纤维化、类风湿性血管炎、浆膜炎和周围神经病变。RA血清抑制人微血管内皮细胞对TNF-α的反应，通过ICAM-1的表达，MCP-1/CCL 2的释放和核高迁移率族蛋白1的输出进行评估;抗CgA抗体的存在下，这种作用减弱。阻断效果与血清中CgA浓度显著相关。CgA的重组氨基末端部分，对应于残基1-78，对用TNF-α攻击的内皮细胞具有类似的抑制作用。我们的研究结果表明，CgA水平的提高确定患者与关节外参与，并揭示了一个负反馈回路，限制了激活的内皮细胞在RA。J. Leukoc. 85：81-87; 2009.
TNF-alpha plays an important role in the natural history of rheumatoid arthritis (RA), a systemic disease characterized by endothelial activation and synovial involvement with bone erosions. Neuroendocrine signals contribute as well to RA, but their role is poorly understood. We measured in 104 RA patients and in an equal number of sex- and age-matched, healthy controls the blood levels of chromogranin A (CgA), a candidate marker linking the neuroendocrine system to TNF-alpha-mediated vascular inflammation. CgA levels were significantly higher in patients with RA and remained stable over time. High levels of CgA were significantly associated with severe extra-articular manifestations, namely pulmonary fibrosis, rheumatoid vasculitis, serositis, and peripheral neuropathy. RA sera curbed the response of human microvascular endothelial cells to TNF-alpha, as assessed by the expression of ICAM-1, the release of MCP-1/CCL2, and the export of nuclear high-mobility group box 1; the effect abated in the presence of anti-CgA antibodies. The efficacy of the blockade was significantly correlated with the CgA concentration in the serum. The recombinant aminoterminal portion of CgA, corresponding to residues 1-78, had similar inhibitory effects on endothelial cells challenged with TNF-alpha. Our results suggest that enhanced levels of CgA identify patients with extra-articular involvement and reveal a negative feedback loop that limits the activation of endothelial cells in RA. J. Leukoc. Biol. 85: 81-87; 2009.