Department of Oral Physiology, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea.
Department of Periodontology, Dental Science Research Institute, School of Dentistry, Chonnam National University, Gwangju, Korea.
J Periodontol. 2022 Mar;93(3):380-391. doi: 10.1002/JPER.21-0178. Epub 2021 Jul 20.
BACKGROUND: Periodontitis is an inflammatory disease caused by multiple disease-associated bacterial species in periodontal tissues. Autophagy is known to modulate various inflammation-driven diseases and inflammatory responses, but the role of autophagy related to the pathogenesis of periodontitis is not fully established. We investigated whether autophagic flux regulated the expression of inflammatory cytokines in the gingiva of periodontitis patients and lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (HGFs) and the underlying mechanism. METHODS: The mRNA and protein expression of proinflammatory cytokines was assessed in human gingival tissues collected from patients with periodontitis and HGFs treated with LPS. The expression of signaling molecules related to autophagy was evaluated by immunofluorescence and Western blot analyses. RESULTS: The expression of interleukin (IL)-6, tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and intercellular adhesion molecule-1 (ICAM-1) was increased in the gingival tissues of patients with periodontitis. LC3B-positive cells, a typical autophagic marker, were increased in the gingival tissues of periodontitis patients and LPS-treated HGFs. The conversion ratio of LC3-I to LC3-II was higher in the gingival tissues associated with periodontitis and LPS-treated HGFs compared to the controls. The autophagy inhibitor 3-methyladenine (3MA) significantly abrogated the LPS-sustained inflammatory effect by reducing the expression of IL-6, TNF-α, COX-2, and ICAM-1 in HGFs. The phosphorylation of protein kinase B (AKT) and protein S6K1 (S6), signals involved in the mTOR-dependent mechanism, was decreased in gingiva derived from periodontitis patients and LPS-treated HGFs. CONCLUSIONS: Autophagy augmented the production of inflammatory cytokines by mTOR inactivation via the AKT signaling pathway in the gingival tissues of patients with periodontitis and LPS-stimulated HGFs. These findings would provide a better understanding of the mechanism by which autophagy regulates the inflammatory response associated with periodontal pathogenesis.
背景：牙周炎是一种由牙周组织中多种与疾病相关的细菌引起的炎症性疾病。自噬被认为可以调节多种炎症驱动的疾病和炎症反应，但自噬与牙周炎发病机制的关系尚不完全明确。我们研究了自噬流是否调节了牙周炎患者牙龈中炎症细胞因子的表达以及脂多糖（LPS）刺激的人牙龈成纤维细胞（HGF），并探讨了其潜在机制。
方法：通过免疫荧光和 Western blot 分析评估了来自牙周炎患者的人牙龈组织和 LPS 处理的 HGF 中与自噬相关的信号分子的 mRNA 和蛋白表达。
结果：牙周炎患者的牙龈组织中白细胞介素（IL）-6、肿瘤坏死因子-α（TNF-α）、环氧化酶-2（COX-2）和细胞间黏附分子-1（ICAM-1）的表达增加。LC3B-阳性细胞，一种典型的自噬标志物，在牙周炎患者的牙龈组织和 LPS 处理的 HGF 中增加。与对照组相比，与牙周炎相关的牙龈组织和 LPS 处理的 HGF 中 LC3-I 向 LC3-II 的转化比例更高。自噬抑制剂 3-甲基腺嘌呤（3MA）通过降低 HGF 中 IL-6、TNF-α、COX-2 和 ICAM-1 的表达，显著阻断了 LPS 持续的炎症作用。与牙周炎患者的牙龈组织和 LPS 处理的 HGF 相比，蛋白激酶 B（AKT）和蛋白 S6K1（S6）的磷酸化（参与 mTOR 依赖性机制的信号）减少。
结论：自噬通过 mTOR 失活增强了牙周炎患者牙龈组织和 LPS 刺激的 HGF 中炎症细胞因子的产生，通过 AKT 信号通路。这些发现将为自噬调节与牙周病发病机制相关的炎症反应的机制提供更好的理解。
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