Defective expression of SIRT1 contributes to sustain inflammatory pathways in the gut
Defective expression of SIRT1 contributes to sustain inflammatory pathways in the gut
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DOI：
10.1038/mi.2014.35
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发表时间：
2014-11-01
影响因子：
8
通讯作者：
Monteleone, G.
中科院分区：
文献类型：
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作者：
Caruso, R.;Marafini, I.;Monteleone, G.
在炎症性肠病(IBD)中，组织损伤是由过度的免疫反应驱动的，但缺乏反调节机制的控制。SIRT1是一种依赖于NAD+的III型脱乙酰酶，它负向调节多种参与免疫炎症通路调控的蛋白的表达，如STAT3、Smad7和NF-kappa B。与正常对照组相比，IBD患者的全部活检组织和固有层单个核细胞(LPMC)中SIRT1RNA和蛋白的表达较弱。对照组LPMC的SIRT1表达受肿瘤坏死因子(TNF)-α和白介素21(IL-21)的抑制，IBD LPMC的SIRT1表达通过中和肿瘤坏死因子-α和IL-21抗体而上调。在英夫利昔单抗治疗成功的IBD患者的粘膜样本中，SIRT1的表达一直在增加。用SIRT1特异性激活剂Cay10591处理IBD LPMC，可减少核因子-kappaB的激活，抑制炎性细胞因子的合成，而SIRT1的抑制剂Ex527可增加对照组LPMC中干扰素-γ的水平。在2，4，6-三硝基苯磺酸或恶唑酮诱导的结肠炎小鼠中，SIRT1也被降低。Cay10591预防和治愈实验性结肠炎，而Ex527通过调节T细胞衍生细胞因子反应而加重疾病。数据表明，SIRT1在IBD患者和结肠炎小鼠中表达下调，并表明SIRT1激活可以帮助减弱肠道中的炎症信号。
In inflammatory bowel disease (IBD), tissue damage is driven by an excessive immune response, poorly controlled by counter-regulatory mechanisms. SIRT1, a class III NAD + -dependent deacetylase, regulates negatively the expression of various proteins involved in the control of immune-inflammatory pathways, such as Stat3, Smad7, and NF-kappa B. Here we examined the expression, regulation, and function of SIRT1 in IBD. SIRT1 RNA and protein expression was less pronounced in whole biopsies and lamina propria mononuclear cells (LPMCs) of IBD patients in comparison with normal controls. SIRT1 expression was downregulated in control LPMC by tumor necrosis factor (TNF)-alpha and interleukin (IL)-21, and upregulated in IBD LPMC by neutralizing TNF-alpha and IL-21 antibodies. Consistently, SIRT1 expression was increased in mucosal samples taken from IBD patients successfully treated with Infliximab. Treatment of IBD LPMC with Cay10591, a specific SIRT1 activator, reduced NF-kappa B activation and inhibited inflammatory cytokine synthesis, whereas Ex527, an inhibitor of SIRT1, increased interferon (IFN)-gamma in control LPMC. SIRT1 was also reduced in mice with colitis induced by 2,4,6-trinitrobenzenesulphonic acid or oxazolone. Cay10591 prevented and cured experimental colitis whereas Ex527 exacerbated disease by modulating T cell-derived cytokine response. Data indicate that SIRT1 is downregulated in IBD patients and colitic mice and suggest that SIRT1 activation can help attenuate inflammatory signals in the gut.