Zhu Tong, Liu Tian-Jing, Shi Yong-Yan, Zhao Qun
Department of Pediatric Orthopedics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China.
Int J Mol Med. 2015 May;35(5):1213-8. doi: 10.3892/ijmm.2015.2150. Epub 2015 Mar 20.
Increasing epidemiological data have suggested a link between vitamin D deficiency and the incidence of inflammatory bowel disease (IBD). In the present study, we confirmed that vitamin D deficiency, as well as the decreased local expression of vitamin D receptor (VDR), was prevalent in an IBD cohort. The excessive apoptosis of intestinal epithelial cells (IECs) partly accounts for the development of colonic inflammation and eventually results in IBD. Based on the established inhibitory effects of the vitamin D/VDR pathway on IEC apoptosis, we treated mice with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis with paricalcitol, a vitamin D analog, in order to investigate the mechanisms responsible for the inhibitory effects of the vitamin D/VDR pathway. We observed that following treatment with vitamin D, the mice presented with only minor bodyweight loss, and the mice also showed improved histological scores and decreased intestinal epithelial permeability compared with the vehicle-treated group. The colonic mRNA expression of inflammatory cytokines and chemokines was markedly suppressed, indicating less severe colitis in the vitamin D-treated mice. Subsequently, we investigated p53 upregulated modulator of apoptosis (PUMA) and p53, two major independent pathways of apoptosis, as well as caspase-3. We found that the vitamin D-treated mice had lower expression levels of caspase-3 than the vehicle-treated mice. PUMA expression showed the same tendency; however, the p53 protein level was not altered. The present study indicates that vitamin D attenuates the development of TNBS-induced colitis by inhibiting the apoptosis of IECs. The mechanisms involved include the downregulation of PUMA expression. Our data provide experimental support for the clinical trials of vitamin D intervention in patients with IBD.
越来越多的流行病学数据表明维生素D缺乏与炎症性肠病（IBD）的发病率之间存在关联。在本研究中，我们证实维生素D缺乏以及维生素D受体（VDR）的局部表达降低在IBD队列中普遍存在。肠上皮细胞（IECs）的过度凋亡部分解释了结肠炎症的发展，并最终导致IBD。基于维生素D/VDR途径对IEC凋亡的既定抑制作用，我们用维生素D类似物帕立骨化醇治疗2,4,6-三硝基苯磺酸（TNBS）诱导的结肠炎小鼠，以研究维生素D/VDR途径产生抑制作用的机制。我们观察到，用维生素D治疗后，小鼠仅出现轻微体重减轻，并且与载体处理组相比，小鼠的组织学评分有所改善，肠上皮通透性降低。炎症细胞因子和趋化因子的结肠mRNA表达明显受到抑制，表明维生素D治疗的小鼠结肠炎较轻。随后，我们研究了凋亡的两个主要独立途径——p53上调凋亡调节因子（PUMA）和p53以及半胱天冬酶-3。我们发现，维生素D治疗的小鼠中半胱天冬酶-3的表达水平低于载体处理的小鼠。PUMA表达呈现相同趋势；然而，p53蛋白水平未改变。本研究表明，维生素D通过抑制IEC凋亡减轻TNBS诱导的结肠炎的发展。涉及的机制包括PUMA表达的下调。我们的数据为IBD患者维生素D干预的临床试验提供了实验支持。
