The Immunopharmacology Research Group, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital, Tampere, Finland.
Inflamm Res. 2023 Jul;72(7):1327-1339. doi: 10.1007/s00011-023-01750-y. Epub 2023 Jun 29.
Transient Receptor Potential Ankyrin 1 (TRPA1) is a cation channel that mediates pain, itch, cough, and neurogenic inflammation in response to pungent compounds such as acrolein in cigarette smoke. TRPA1 is also activated by endogenous factors and promotes inflammation in asthma models. We have recently shown that TRPA1 is upregulated by inflammatory cytokines in A549 human lung epithelial cells. Here, we explored the effects of Th1 and Th2-type inflammation on TRPA1.
TRPA1 expression and function was studied in A549 human lung epithelial cells. To induce inflammation, the cells were exposed to a combination of cytokines TNF-α and IL-1β; and to model Th1 or Th2-type responses, IFN-γ or IL-4/IL-13 was added, respectively. TRPA1 expression (measured by RT-PCR and Western blot) and function (assessed by Fluo-3AM intracellular calcium measurement) was enhanced under the influence of TNF-α + IL-1β. IFN-γ further enhanced TRPA1 expression and function, whereas IL-4 and IL-13 suppressed them. The effects of IFN-γ and IL-4 on TRPA1 expression were reversed by the Janus kinase (JAK) inhibitors baricitinib and tofacitinib, and those of IL-4 also by the STAT6 inhibitor AS1517499. The glucocorticoid dexamethasone downregulated TRPA1 expression, whereas the PDE4 inhibitor rolipram had no effect. Under all conditions, TRPA1 blockade was found to reduce the production of LCN2 and CXCL6.
TRPA1 expression and function in lung epithelial cells was upregulated under inflammatory conditions. IFN-γ further increased TRPA1 expression while IL-4 and IL-13 suppressed that in a JAK-STAT6 dependent manner which is novel. TRPA1 also modulated the expression of genes relevant to innate immunity and lung disease. We propose that the paradigm of Th1 and Th2 inflammation is a major determinant of TRPA1 expression and function, which should be considered when targeting TRPA1 for pharmacotherapy in inflammatory (lung) disease.
瞬时受体电位阳离子通道 ankryn 1（TRPA1）是一种阳离子通道，可介导疼痛、瘙痒、咳嗽和神经源性炎症，对香烟烟雾中的丙烯醛等刺激性化合物产生反应。TRPA1 也被内源性因子激活，并在哮喘模型中促进炎症。我们最近表明，TRPA1 在 A549 人肺上皮细胞中由炎症细胞因子上调。在这里，我们探讨了 Th1 和 Th2 型炎症对 TRPA1 的影响。
在 A549 人肺上皮细胞中研究了 TRPA1 的表达和功能。为了诱导炎症，细胞暴露于 TNF-α 和 IL-1β 的组合中；为了模拟 Th1 或 Th2 型反应，分别加入 IFN-γ 或 IL-4/IL-13。在 TNF-α+IL-1β 的影响下，TRPA1 的表达（通过 RT-PCR 和 Western blot 测量）和功能（通过 Fluo-3AM 细胞内钙测量评估）增强。IFN-γ 进一步增强了 TRPA1 的表达和功能，而 IL-4 和 IL-13 则抑制了它。IFN-γ 和 IL-4 对 TRPA1 表达的影响可被 Janus 激酶（JAK）抑制剂巴瑞替尼和托法替尼逆转，而 IL-4 的影响也可被 STAT6 抑制剂 AS1517499 逆转。糖皮质激素地塞米松下调 TRPA1 的表达，而 PDE4 抑制剂罗利普兰则没有影响。在所有条件下，TRPA1 阻断被发现可降低 LCN2 和 CXCL6 的产生。
在炎症条件下，肺上皮细胞中的 TRPA1 表达和功能上调。IFN-γ 进一步增加了 TRPA1 的表达，而 IL-4 和 IL-13 则以 JAK-STAT6 依赖的方式抑制了其表达，这是新颖的。TRPA1 还调节与先天免疫和肺部疾病相关的基因的表达。我们提出 Th1 和 Th2 炎症的范例是 TRPA1 表达和功能的主要决定因素，在针对炎症（肺部）疾病的 TRPA1 药物治疗时应考虑这一点。
