Matsumoto Takahiro, Matsushima Yuki, Toda Masaaki, Roeen Ziaurahman, D'Alessandro-Gabazza Corina N, Hinneh Josephine A, Harada Etsuko, Yasuma Taro, Yano Yutaka, Urawa Masahito, Kobayashi Tetsu, Taguchi Osamu, Gabazza Esteban C
Department of Immunology, Mie University Graduate School of Medicine, Tsu, Mie Prefecture, Japan ; BONAC Corporation, BIO Factory 4F, Fukuoka, Japan.
Department of Immunology, Mie University Graduate School of Medicine, Tsu, Mie Prefecture, Japan.
J Asthma Allergy. 2015 May 7;8:29-37. doi: 10.2147/JAA.S75261. eCollection 2015.
Previous studies have demonstrated the beneficial activity of activated protein C in allergic diseases including bronchial asthma and rhinitis. However, the exact mechanism of action of activated protein C in allergies is unclear. In this study, we hypothesized that pharmacological doses of activated protein C can modulate allergic inflammation by inhibiting dendritic cells.
Dendritic cells were prepared using murine bone marrow progenitor cells and human peripheral monocytes. Bronchial asthma was induced in mice that received intratracheal instillation of ovalbumin-pulsed dendritic cells.
Activated protein C significantly increased the differentiation of tolerogenic plasmacytoid dendritic cells and the secretion of type I interferons, but it significantly reduced lipopolysaccharide-mediated maturation and the secretion of inflammatory cytokines in myeloid dendritic cells. Activated protein C also inhibited maturation and the secretion of inflammatory cytokines in monocyte-derived dendritic cells. Activated protein C-treated dendritic cells were less effective when differentiating naïve CD4 T-cells from Th1 or Th2 cells, and the cellular effect of activated protein C was mediated by its receptors. Mice that received adoptive transfer of activated protein C-treated ovalbumin-pulsed dendritic cells had significantly less airway hyperresponsiveness, significantly decreased lung concentrations of Th1 and Th2 cytokines, and less plasma concentration of immunoglobulin E when compared to control mice.
These results suggest that dendritic cells mediate the immunosuppressive effect of activated protein C during allergic inflammation.
先前的研究已证明活化蛋白C在包括支气管哮喘和鼻炎在内的过敏性疾病中具有有益作用。然而，活化蛋白C在过敏中的确切作用机制尚不清楚。在本研究中，我们假设药理剂量的活化蛋白C可通过抑制树突状细胞来调节过敏性炎症。
使用小鼠骨髓祖细胞和人外周单核细胞制备树突状细胞。通过气管内滴注卵清蛋白脉冲树突状细胞诱导小鼠患支气管哮喘。
活化蛋白C显著增加了耐受性浆细胞样树突状细胞的分化和I型干扰素的分泌，但显著降低了髓样树突状细胞中脂多糖介导的成熟和炎性细胞因子的分泌。活化蛋白C还抑制单核细胞来源的树突状细胞的成熟和炎性细胞因子的分泌。经活化蛋白C处理的树突状细胞在将初始CD4 T细胞分化为Th1或Th2细胞时效果较差，且活化蛋白C的细胞作用由其受体介导。与对照小鼠相比，接受经活化蛋白C处理的卵清蛋白脉冲树突状细胞过继转移的小鼠气道高反应性显著降低，肺中Th1和Th2细胞因子浓度显著降低，血浆免疫球蛋白E浓度也较低。
这些结果表明，在过敏性炎症期间，树突状细胞介导了活化蛋白C的免疫抑制作用。
