Department of Allergy and Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
Eur J Immunol. 2012 Aug;42(8):2121-31. doi: 10.1002/eji.201242398.
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-α-induced, but not IL-1β-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-α-mediated early signaling events of the NF-κB and MAPK pathways but it potently inhibited gene expression of G-CSF and IL-6 12 h after TNF-α-stimulation. Interestingly, suppression of the G-CSF and IL-6 gene expression correlated closely with functional inhibition of a transcription factor, C/EBPδ, 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.
高剂量静脉注射免疫球蛋白（IVIG）用于治疗自身免疫性和炎症性疾病，包括川崎病（KD）。尽管 IVIG 对巨噬细胞等血细胞的免疫调节作用已得到充分研究，但它对组织细胞的影响仍不清楚。在这里，我们表明高剂量 IgG 特异性且完全抑制了培养的人冠状动脉内皮细胞（HCAEC）中 TNF-α诱导但不抑制 IL-1β诱导的促炎细胞因子如 G-CSF 和 IL-6 的分泌。高剂量 IgG 不抑制 TNF-α介导的 NF-κB 和 MAPK 途径的早期信号事件，但它强烈抑制 TNF-α刺激后 12 小时 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/EBPδ 的功能抑制密切相关，其结合位点在 G-CSF 和 IL-6 的启动子中对于它们的转录激活至关重要。此外，完整 IgG 对 HCAEC 的抑制作用主要通过其 F(ab')(2)片段而不是 Fc 片段发挥作用。这些发现表明，IVIG 对 KD 患者的临床疗效至少部分归因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。
