Department of Maxillofacial Tissue Regeneration, School of Dentistry and Institute of Oral Biology, Kyung Hee University, Seoul, Republic of Korea.
Clin Exp Immunol. 2012 Apr;168(1):113-24. doi: 10.1111/j.1365-2249.2011.04549.x.
Recently, Sirtuin 1 (SIRT1) has been implicated in the molecular control of ageing and immune response. Although the remodelling of periodontal ligament (PDL) in response to mechanical stress (MS) is mediated by several host factors, including cytokines and chemokines, the transmission of mechanical stimuli into specific cellular activity is still not understood fully. This study aimed to investigate the effects of MS, particularly cyclic strain, on immune response genes, as well as SIRT1 and its signal transduction pathways, in human PDL cells. MS up-regulated the expression of SIRT1 and immune response genes encoding cytokines [tumour necrosis factor (TNF)-α, interleukin (IL)-1β], chemokines [IL-8, monocyte cheoattractant protein (CCL)-20], defensins [human β-defensin (hBD)-2, hBD-3] and Toll-like receptors (TLR-2 and TLR-4) in a force- and time-dependent manner. The SIRT1 inducers resveratrol and isonicotinamide attenuated MS-induced cytokine and chemokine expression, but enhanced the expression of defensins and TLRs. Blockade of SIRT1 activity by the SIRT1 inhibitors sirtinol and nicotinamide and down-regulation of SIRT1 expression by SIRT1 siRNA reduced the stimulatory effects of MS on defensins and TLRs, but increased its effects on cytokines and chemokines. MS induced activation of protein kinase B (Akt), protein kinase C (PKC), nuclear factor (NF)-κB and p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). Treatment with the anti-oxidants N-acetylcysteine and glutathione inhibited MS-induced reactive oxygen species production and expression of cytokines, chemokines, defensins and TLRs. These results suggest that MS activates human PDL cells to express immune/defence genes encoding cytokines, chemokines, defensins and TLRs via a SIRT1 pathway.
最近，Sirtuin 1（SIRT1）被认为参与了衰老和免疫反应的分子调控。尽管牙周韧带（PDL）对机械应力（MS）的重塑是由多种宿主因素介导的，包括细胞因子和趋化因子，但机械刺激向特定细胞活动的传递仍不完全清楚。本研究旨在探讨 MS，特别是循环应变，对人牙周膜细胞中免疫反应基因以及 SIRT1 及其信号转导途径的影响。MS 以力和时间依赖的方式上调 SIRT1 和编码细胞因子[肿瘤坏死因子（TNF）-α、白细胞介素（IL）-1β]、趋化因子[IL-8、单核细胞趋化蛋白（CCL）-20]、防御素[人β-防御素（hBD）-2、hBD-3]和 Toll 样受体（TLR-2 和 TLR-4）的表达。SIRT1 诱导剂白藜芦醇和异烟酰胺减弱了 MS 诱导的细胞因子和趋化因子表达，但增强了防御素和 TLR 的表达。SIRT1 抑制剂 Sirtinol 和烟酰胺以及 SIRT1 siRNA 下调 SIRT1 表达阻断 SIRT1 活性，降低了 MS 对防御素和 TLR 的刺激作用，但增加了其对细胞因子和趋化因子的作用。MS 诱导蛋白激酶 B（Akt）、蛋白激酶 C（PKC）、核因子（NF）-κB 和 p38 丝裂原激活蛋白激酶（MAPK）、c-Jun N 端激酶（JNK）和细胞外信号调节激酶（ERK）的激活。抗氧化剂 N-乙酰半胱氨酸和谷胱甘肽的处理抑制了 MS 诱导的活性氧产生和细胞因子、趋化因子、防御素和 TLR 的表达。这些结果表明，MS 通过 SIRT1 途径激活人牙周膜细胞表达免疫/防御基因，编码细胞因子、趋化因子、防御素和 TLR。
