Departamento de Inmunología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, ENCB-IPN, Mexico City, Mexico.
Laboratorio de Inmunología Integrativa, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico.
J Leukoc Biol. 2020 Sep;108(3):859-866. doi: 10.1002/JLB.3AB0320-547RR. Epub 2020 Jun 1.
Mast cell activation through the high-affinity IgE receptor (FcεRI) plays a central role in allergic reactions. FcεRI-mediated activation triggers multiple signaling pathways leading to degranulation and synthesis of different inflammatory mediators. IgE-mediated mast cell activation can be modulated by different molecules, including several drugs. Herein, we investigated the immunomodulatory activity of the histone deacetylase inhibitor valproic acid (VPA) on IgE-mediated mast cell activation. To this end, bone marrow-derived mast cells (BMMC) were sensitized with IgE and treated with VPA followed by FcεRI cross-linking. The results indicated that VPA reduced mast cell IgE-dependent degranulation and cytokine release. VPA also induced a significant reduction in the cell surface expression of FcεRI and CD117, but not other mast cell surface molecules. Interestingly, VPA treatment inhibited the phosphorylation of PLCγ2, a key signaling molecule involved in IgE-mediated degranulation and cytokine secretion. However, VPA did not affect the phosphorylation of other key components of the FcεRI signaling pathway, such as Syk, Akt, ERK1/2, or p38. Altogether, our data demonstrate that VPA affects PLCγ2 phosphorylation, which in turn decreases IgE-mediated mast cell activation. These results suggest that VPA might be a key modulator of allergic reactions and might be a promising therapeutic candidate.
肥大细胞通过高亲和力 IgE 受体 (FcεRI) 的激活在过敏反应中起着核心作用。FcεRI 介导的激活触发多种信号通路，导致脱颗粒和不同炎症介质的合成。IgE 介导的肥大细胞激活可以通过多种分子进行调节，包括几种药物。在此，我们研究了组蛋白去乙酰化酶抑制剂丙戊酸（VPA）对 IgE 介导的肥大细胞激活的免疫调节活性。为此，用 IgE 敏化骨髓来源的肥大细胞（BMMC），并用 VPA 处理，然后进行 FcεRI 交联。结果表明，VPA 减少了肥大细胞 IgE 依赖性脱颗粒和细胞因子释放。VPA 还诱导 FcεRI 和 CD117 的细胞表面表达显著减少，但其他肥大细胞表面分子不受影响。有趣的是，VPA 处理抑制了 PLCγ2 的磷酸化，PLCγ2 是 IgE 介导的脱颗粒和细胞因子分泌的关键信号分子。然而，VPA 不影响 FcεRI 信号通路的其他关键组成部分的磷酸化，如 Syk、Akt、ERK1/2 或 p38。总之，我们的数据表明，VPA 影响 PLCγ2 的磷酸化，进而减少 IgE 介导的肥大细胞激活。这些结果表明，VPA 可能是过敏反应的关键调节剂，并且可能是一种有前途的治疗候选药物。
