Anti-inflammatory effects of high-dose IgG on TNF-α-activated human coronary artery endothelial cells
Anti-inflammatory effects of high-dose IgG on TNF-α-activated human coronary artery endothelial cells
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DOI：
10.1002/eji.201242398
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发表时间：
2012-08-01
影响因子：
5.4
通讯作者：
Abe, Jun
中科院分区：
文献类型：
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作者：
Matsuda, Akio;Morita, Hideaki;Abe, Jun
高剂量输注IgG（IVIG）用于治疗自身免疫性和炎性疾病，包括川崎（KD）。虽然IVIG对血细胞如巨噬细胞的免疫调节作用已经得到了很好的研究，但其对组织细胞的作用仍不清楚。在这里，我们表明，高剂量的IgG特异性和完全抑制TNF-α诱导的，但不是IL-1 β诱导的，促炎细胞因子，如G-CSF和IL-6的分泌培养的人冠状动脉内皮细胞（HCAECs）。高剂量的IgG没有抑制TNF-α介导的NF-？B和MAPK途径，但在TNF-α刺激后12小时，它有效地抑制G-CSF和IL-6的基因表达。有趣的是，G-CSF和IL-6基因表达的抑制与转录因子C/EBPd的功能抑制密切相关，C/EBPd在G-CSF和IL-6启动子中的结合位点已被证明对其转录激活至关重要。此外，完整IgG对HCAEC的抑制作用主要是通过其F（ab）2片段而不是其Fc片段来实现的。这些结果表明，IVIG对KD患者的临床效果至少部分是由于其对冠状动脉内皮的直接抗炎作用，这是KD发病机制中的主要病变部位。
High-dose infusion of IgG (IVIG) is used to treat autoimmune and inflammatory diseases, including Kawasaki disease (KD). Although the immunomodulatory effects of IVIG on blood cells such as macrophages have been well studied, its effects on tissue cells remain unclear. Here, we show that high-dose IgG specifically and completely inhibited TNF-a-induced, but not IL-1 beta-induced, secretion of proinflammatory cytokines such as G-CSF and IL-6 by cultured human coronary artery endothelial cells (HCAECs). High-dose IgG did not inhibit TNF-a-mediated early signaling events of the NF-?B and MAPK pathways but it potently inhibited gene expression of G-CSF and IL-6 12 h after TNF-a-stimulation. Interestingly, suppression of the G-CSF and IL-6 gene expression correlated closely with functional inhibition of a transcription factor, C/EBPd, whose binding sites in the promoters of G-CSF and IL-6 have been shown to be critical for their transcriptional activation. Furthermore, the inhibitory effect of intact IgG on HCAECs was exerted mainly via its F(ab)2 fragment, and not its Fc fragment. These findings suggest that the clinical effects of IVIG on KD patients are at least in part due to its direct anti-inflammatory effects on the coronary endothelium, which is a major lesion site in the pathogenesis of KD.