β-肾上腺素能刺激可促进唾液腺上皮细胞内质网应激依赖性炎症程序。

IF 3.4 3区 医学 Q3 IMMUNOLOGY Clinical and experimental immunology Pub Date : 2024-09-16 DOI:10.1093/cei/uxae054
Kalliopi Moustaka, Athanasios Stergiopoulos, Roxane Tenta, Sophia Havaki, Stergios Katsiougiannis, Fotini N Skopouli
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引用次数: 0

摘要

研究了β-肾上腺素能刺激人唇小唾液腺上皮细胞(LMSGEC)对IL-6产生的影响及其与内质网(ER)应激的依赖关系。用肾上腺素刺激斯约格伦综合征(SS)患者和对照组培养的原代小唾液腺上皮细胞,并用 qPCR 和 ELISA 评估 IL-6 的表达。通过 qPCR 检测了培养的 LMSGEC 中 β-ARs 的表达,同时通过免疫荧光检测了 LMSG 中肾上腺素受体和 cAMP 的水平。透射电子显微镜(TEM)对ER进行了评估,Western印迹对ER应激进行了检测。在应用牛磺脱氧胆酸(TUDCA)和沉默 PKR 样 ER 激酶(PERK)和激活转录因子 4(ATF4)RNA 缓解 ER 压力后,评估了肾上腺素能诱导培养的 LMSGEC 产生的 IL-6。LMSGEC在受到β肾上腺素能刺激后IL-6的表达上调,而沉默肾上腺素受体则会下调IL-6的表达。ER应激的改善以及PERK/ATF4的沉默阻止了肾上腺素诱导的IL-6上调。与对照组相比,肾上腺素能刺激导致 SS 患者的 LMSGEC 分泌出更高且持续的 IL-6 水平。在 SS 患者的 LMSGEC 中,肾上腺素能信号传导内源性增强(β-ARs 原位表达、培养的 LMSGEC 细胞内 cAMP)。同时,SS-LMSGEC 表达扩张的 ER(TEM)和更高水平的 GRP78/BiP。ER应激的PERK/ATF4通路成为肾上腺素刺激LMSGEC产生IL-6的重要介质。在 SS-LMSGEC 中观察到的内源性肾上腺素能激活增强和ER受压可能有助于这些细胞在肾上腺素能刺激后持续产生 IL-6。
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Beta-adrenergic stimulation promotes an endoplasmic reticulum stress-dependent inflammatory program in salivary gland epithelial cells.

The effect of beta-adrenergic stimulation on human labial minor salivary gland epithelial cells (LMSGEC) on IL-6 production and its dependency on endoplasmic reticulum (ER) stress were investigated. Primary LMSGEC from Sjögren's syndrome (SS) patients and controls in culture were stimulated with epinephrine and IL-6 expression was evaluated by qPCR and ELISA. The expression of β-ARs in cultured LMSGEC was tested by qPCR, while adrenoceptors and cAMP levels were examined in LMSGs by immunofluorescence. ER evaluation was performed by transmission electron microscopy (TEM) and ER stress by western blot. Epinephrine-induced IL-6 production by cultured LMSGEC was evaluated after alleviation of the ER stress by applying tauroursodeoxycholic acid (TUDCA) and silencing of PKR-like ER kinase (PERK) and activating transcription factor 4 (ATF4) RNAs. Expression of IL-6 by LMSGEC was upregulated after β-adrenergic stimulation, while the silencing of adrenoreceptors downregulated IL-6. The amelioration of ER stress, as well as the silencing of PERK/ATF4, prevented epinephrine-induced upregulation of IL-6. Adrenergic stimulation led to higher and sustained IL-6 levels secreted by LMSGEC of SS patients compared to controls. Adrenergic signaling was endogenously enhanced in LMSGEC of SS patients (expression of β-ARs in situ, intracellular cAMP in cultured LMSGEC). In parallel, SS-LMSGEC expressed dilated ER (TEM) and higher levels of GRP78/BiP. PERK/ATF4 pathway of the ER stress emerged as a considerable mediator of adrenergic stimulation for IL-6 production by the LMSGEC. An enhanced endogenous adrenergic activation and a stressed ER observed in SS-LMSGEC may contribute to a sustained IL-6 production by these cells after adrenergic stimulation.

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来源期刊
CiteScore
8.40
自引率
2.20%
发文量
101
审稿时长
3-8 weeks
期刊介绍: Clinical & Experimental Immunology (established in 1966) is an authoritative international journal publishing high-quality research studies in translational and clinical immunology that have the potential to transform our understanding of the immunopathology of human disease and/or change clinical practice. The journal is focused on translational and clinical immunology and is among the foremost journals in this field, attracting high-quality papers from across the world. Translation is viewed as a process of applying ideas, insights and discoveries generated through scientific studies to the treatment, prevention or diagnosis of human disease. Clinical immunology has evolved as a field to encompass the application of state-of-the-art technologies such as next-generation sequencing, metagenomics and high-dimensional phenotyping to understand mechanisms that govern the outcomes of clinical trials.
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