Yang Chongbo, He Zhao, Zhang Qunye, Lu Ming, Zhao Jiajun, Chen Wenbin, Gao Ling
Department of Endocrinology, Shandong Provincial Hospital affiliated to Shandong First Medical University, Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Jinan, Shandong, China.
Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Endocrinology. 2021 Aug 1;162(8). doi: 10.1210/endocr/bqab077.
Thyroid-stimulating hormone (TSH) treatment activates inhibitor of NF-κB/nuclear factor κB (IκB/NFκB) and extracellular signal-regulated kinase (ERK)-P38 in macrophages, but how these pathways are activated, and how they contribute to the proinflammatory effect of TSH on macrophages remain unknown. The TSH receptor (TSHR) is coupled to 4 subfamilies of G proteins (Gs, Gi/o, Gq/11, and G12/13) for its downstream signaling. This study investigated the G protein subtypes responsible for the proinflammatory effect of TSH on macrophages. qPCR showed that Gi2, Gi3, Gas, Gq, G11, G12, G13, and G15 are abundantly expressed by macrophages. The contribution of different G protein pathways to the proinflammatory effect was studied by the corresponding inhibitors or siRNA interference. While TSH-induced IκB phosphorylation was not inhibited by Gs inhibitor NF449, Gi inhibitor pertussis toxin, or Gq or G11 siRNA, it was blocked by phospholipase C inhibitor U73122 or G15 siRNA interference. TSH-induced ERK and P38 phosphorylation was blocked by G13 but not G12 siRNA interference. Interference of either G13 or G15 could block the proinflammatory effect of TSH on macrophages. The present study demonstrate that TSH activates macrophage inflammation by the G13/ERK-P38/Rho GTPase and G15/phospholipase C (PLC)/protein kinases C (PKCs)/IκB pathways.
促甲状腺激素（TSH）治疗可激活巨噬细胞中的核因子κB抑制蛋白/核因子κB（IκB/NFκB）和细胞外信号调节激酶（ERK）-P38，但这些信号通路是如何被激活的，以及它们如何促进TSH对巨噬细胞的促炎作用仍不清楚。TSH受体（TSHR）通过4个G蛋白亚家族（Gs、Gi/o、Gq/11和G12/13）进行下游信号传导。本研究调查了介导TSH对巨噬细胞促炎作用的G蛋白亚型。定量聚合酶链反应（qPCR）显示，巨噬细胞中大量表达Gi2、Gi3、Gas、Gq、G11、G12、G13和G15。通过相应的抑制剂或小干扰RNA（siRNA）研究了不同G蛋白信号通路对促炎作用的贡献。虽然Gs抑制剂NF449、Gi抑制剂百日咳毒素或Gq或G11的siRNA均未抑制TSH诱导的IκB磷酸化，但磷脂酶C抑制剂U73122或G15的siRNA干扰可阻断该过程。G13的siRNA干扰可阻断TSH诱导的ERK和P38磷酸化，而G12的siRNA干扰则无此作用。干扰G13或G15均可阻断TSH对巨噬细胞的促炎作用。本研究表明，TSH通过G13/ERK-P38/ Rho鸟苷三磷酸酶（GTPase）和G15/磷脂酶C（PLC）/蛋白激酶C（PKC）/IκB信号通路激活巨噬细胞炎症反应。
