In periodontal disease (PD), bacterial biofilms cause gingival inflammation leading to bone loss. In health, αvβ6 integrin in junctional epithelium maintains anti-inflammatory transforming growth factor-β1 (TGF-β1) signaling, whereas its expression is lost in PD. Bacterial biofilms suppress β6 integrin expression in cultured gingival epithelial cells (GECs) by attenuating TGF-β1 signaling, leading to enhanced pro-inflammatory response. In the present study, we show that GEC exposure to biofilm induced activation of mitogen-activated protein kinases and epidermal growth factor receptor (EGFR). Inhibition of EGFR and ERK stunted both the biofilm-induced ITGB6 suppression and IL1B stimulation. Furthermore, biofilm induced the expression of endogenous EGFR ligands that suppressed ITGB6 and stimulated IL1B expression, indicating that the biofilm effects were mediated by autocrine EGFR signaling. Biofilm and EGFR ligands induced inhibitory phosphorylation of TGF-β1 signaling mediator Smad3 at S208. Overexpression of a phosphorylation-defective mutant of Smad3 (S208A) blunted the β6 integrin suppression. Furthermore, inhibition of EGFR signaling significantly reduced bone loss and inflammation in an experimental PD model. Thus, EGFR inhibition may provide a target for clinical therapies to prevent inflammation and bone loss in PD.

中文翻译：

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表皮生长因子受体信号传导抑制αvβ6整联蛋白并促进牙周炎症和骨质流失。

在牙周疾病（PD）中，细菌生物膜引起牙龈发炎，导致骨质流失。在健康方面，关节上皮中的αvβ6整联蛋白维持抗炎转化生长因子-β1（TGF-β1）信号传导，而其表达在PD中丢失。细菌生物膜通过减弱TGF-β1信号传导抑制培养的牙龈上皮细胞（GEC）中β6整合素的表达，从而导致促炎反应增强。在本研究中，我们显示GEC暴露于生物膜可诱导丝裂原活化蛋白激酶和表皮生长因子受体（EGFR）活化。EGFR和ERK的抑制阻碍了生物膜诱导的ITGB6抑制和IL1B刺激。此外，生物膜可诱导内源性EGFR配体的表达，从而抑制ITGB6并刺激IL1B的表达，表明生物膜作用是由自分泌EGFR信号传导介导的。生物膜和EGFR配体在S208诱导TGF-β1信号传导介质Smad3的抑制性磷酸化。Smad3（S208A）的磷酸化缺陷突变体的过表达减弱了β6整联蛋白的抑制作用。此外，在实验性PD模型中，EGFR信号转导的抑制作用显着降低了骨丢失和炎症。因此，EGFR抑制可能为临床疗法提供目标，以预防PD中的炎症和骨质流失。在实验性PD模型中，EGFR信号转导的抑制作用显着减少了骨丢失和炎症。因此，EGFR抑制可能为临床疗法提供目标，以预防PD中的炎症和骨质流失。在实验性PD模型中，EGFR信号转导的抑制作用显着减少了骨丢失和炎症。因此，EGFR抑制可能为临床疗法提供目标，以预防PD中的炎症和骨质流失。