Department of Health Sciences, Faculty of Applied Health Sciences, Cairns Family Health and Bioscience Research Complex, Brock University, Niagara Region, Ontario, Canada.
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
J Leukoc Biol. 2020 Apr;107(4):649-661. doi: 10.1002/JLB.2A0220-401RRR. Epub 2020 Feb 28.
Mast cells drive the inappropriate immune response characteristic of allergic inflammatory disorders via release of pro-inflammatory mediators in response to environmental cues detected by the IgE-FcεRI complex. The role of TGF-β-activated kinase 1 (TAK1), a participant in related signaling in other contexts, remains unknown in allergy. We detect novel activation of TAK1 at Ser412 in response to IgE-mediated activation under SCF-c-kit potentiation in a mast cell-driven response characteristic of allergic inflammation, which is potently blocked by TAK1 inhibitor 5Z-7-oxozeaenol (OZ). We, therefore, interrogated the role of TAK1 in a series of mast cell-mediated responses using IgE-sensitized murine bone marrow-derived mast cells, stimulated with allergen under several TAK1 inhibition strategies. TAK1 inhibition by OZ resulted in significant impairment in the phosphorylation of MAPKs p38, ERK, and JNK; and mediation of the NF-κB pathway via IκBα. Impaired gene expression and near abrogation in release of pro-inflammatory cytokines TNF, IL-6, IL-13, and chemokines CCL1, and CCL2 was detected. Finally, a significant inhibition of mast cell degranulation, accompanied by an impairment in calcium mobilization, was observed in TAK1-inhibited cells. These results suggest that TAK1 acts as a signaling node, not only linking the MAPK and NF-κB pathways in driving the late-phase response, but also initiation of the degranulation mechanism of the mast cell early-phase response following allergen recognition and may warrant consideration in future therapeutic development.
肥大细胞通过 IgE-FcεRI 复合物检测到的环境线索释放促炎介质，从而驱动过敏炎症性疾病中不适当的免疫反应。转化生长因子-β激活激酶 1（TAK1）在其他相关信号通路中扮演着重要角色，但在过敏反应中其作用尚不清楚。我们在肥大细胞驱动的过敏炎症反应中，检测到 TAK1 在 Ser412 处的新型激活，这是对 IgE 介导的激活和干细胞因子-c-kit 增强的反应，而 TAK1 抑制剂 5Z-7-氧杂嗪醇（OZ）可强烈抑制该反应。因此，我们使用 IgE 致敏的鼠骨髓来源的肥大细胞，在几种 TAK1 抑制策略下，用变应原刺激，研究了 TAK1 在一系列肥大细胞介导的反应中的作用。OZ 对 TAK1 的抑制导致 MAPKs p38、ERK 和 JNK 的磷酸化以及 IκBα介导的 NF-κB 途径受到显著损害。还检测到基因表达受损和促炎细胞因子 TNF、IL-6、IL-13 以及趋化因子 CCL1 和 CCL2 的释放几乎被阻断。最后，在 TAK1 抑制的细胞中观察到肥大细胞脱颗粒的显著抑制，同时伴随着钙动员的受损。这些结果表明，TAK1 作为信号节点，不仅在驱动晚期反应中连接 MAPK 和 NF-κB 通路，而且在变应原识别后启动肥大细胞早期反应的脱颗粒机制，这可能值得在未来的治疗开发中考虑。
