SG-SP1 Suppresses Mast Cell-Mediated Allergic Inflammation via Inhibition of FcεRI Signaling
SG-SP1 Suppresses Mast Cell-Mediated Allergic Inflammation via Inhibition of FcεRI Signaling
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DOI：
10.3389/fimmu.2020.00050
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发表时间：
2020-01-28
影响因子：
7.3
通讯作者：
Kim, Sang-Hyun
中科院分区：
文献类型：
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作者：
Kim, Min-Jong;Je, In-Gyu;Kim, Sang-Hyun
背景：随着过敏性疾病数量的增加，寻找新的治疗方法的研究变得更加紧迫。表没食子儿茶素没食子酸酯（Epigallocatechin gallate，EGCG）是绿色茶的主要成分，具有抗炎、抗病毒等多种药理作用。没食子酸（gallic acid，GA）是表没食子儿茶素没食子酸酯（EGCG）的一部分，在以往的研究中已显示出抗过敏性炎症的作用。为了进一步完善GA具有抗过敏作用的初步证据，我们设计了基于GA的SG-SP1，并利用各种动物和体外模型评估SG-SP1对肥大细胞介导的过敏性炎症的影响。（RBL-2 H3：肥大细胞样嗜碱性白血病细胞，以及原代培养的腹膜和骨髓来源的肥大细胞）用于确定SG-SP1（0.1-1 nM）的作用。免疫球蛋白（IG）E诱导的被动皮肤过敏反应和卵白蛋白诱导的全身过敏反应，速发型超敏反应的标准动物模型也被used.Results：在体外，SG-SP 1通过下调细胞内钙水平以浓度依赖性的方式减少肥大细胞的脱粒。SG-SP1可降低活化肥大细胞中炎性细胞因子的表达和分泌。这种抑制作用与抑制林恩、Syk和Akt的磷酸化以及核因子-κ B的核转位有关。由于SG-SP 1对已知的Fc β RI依赖性通路的上游信号传导林恩具有强烈的抑制作用，我们通过表面等离子体共振实验证实了SG-SP 1与高亲和力IgE受体Fc β RI的直接结合。口服SG-SP1可抑制两种过敏反应模型的过敏症状，表现为体温过低、血清IgE、耳朵厚度和组织色素沉着的减少。这种抑制作用是通过降低血清组胺和白细胞介素-4介导的。结论：我们确定了SG-SP 1直接与Fc ε RI相互作用，并建议SG-SP 1通过抑制Fc ε RI信号转导作为肥大细胞介导的过敏性炎症疾病的治疗候选物。
Background: As the number of allergic disease increases, studies to identify new treatments take on new urgency. Epigallocatechin gallate (EGCG), a major component of green tea, has been shown to possess a wide range of pharmacological properties, including anti-inflammation and anti-viral infection. In previous study, gallic acid (GA), a part of EGCG, has shown anti-allergic inflammatory effect. To improve on preliminary evidence that GA has allergy mitigating effect, we designed SG-SP1 based on GA, and aimed to assess the effects of SG-SP1 on mast cell-mediated allergic inflammation using various animal and in vitro models.Methods: For in vitro experiments, various types of IgE-stimulated mast cells (RBL-2H3: mast cell-like basophilic leukemia cells, and primary cultured peritoneal and bone marrow-derived mast cells) were used to determine the role of SG-SP1 (0.1-1 nM). Immunoglobulin (Ig) E-induced passive cutaneous anaphylaxis and ovalbumin-induced systemic anaphylaxis, standard animal models for immediate-type hypersensitivity were also used.Results: For in vitro, SG-SP1 reduced degranulation of mast cells by down-regulating intracellular calcium levels in a concentration-dependent manner. SG-SP1 decreased expression and secretion of inflammatory cytokines in activated mast cells. This suppressive effect was associated with inhibition of the phosphorylation of Lyn, Syk and Akt, and the nuclear translocation of nuclear factor-kappa B. Due to the strong inhibitory effect of SG-SP1 on Lyn, the known upstream signaling to Fc epsilon RI-dependent pathway, we confirmed the direct binding of SG-SP1 to Fc epsilon RI, a high affinity IgE receptor by surface plasmon resonance experiment. Oral administration of SG-SP1 hindered allergic symptoms of both anaphylaxis models evidenced by reduction of hypothermia, serum IgE, ear thickness, and tissue pigmentation. This inhibition was mediated by the reductions in serum histamine and interleukin-4.Conclusions: We determined that SG-SP1 directly interacts with Fc epsilon RI and propose SG-SP1 as a therapeutic candidate for mast cell-mediated allergic inflammatory disorders via inhibition of Fc epsilon RI signaling.