A Role for MYC in Lithium-Stimulated Repair of the Colonic Epithelium After DSS-Induced Damage in Mice
A Role for MYC in Lithium-Stimulated Repair of the Colonic Epithelium After DSS-Induced Damage in Mice
复制标题
DOI：
10.1007/s10620-015-3852-0
复制
发表时间：
2016-02-01
影响因子：
3.1
通讯作者：
Yochum, Gregory S.
中科院分区：
文献类型：
--
作者：
Raup-Konsavage, Wesley M.;Cooper, Timothy K.;Yochum, Gregory S.
慢性炎症破坏溃疡性结肠炎（UC）患者的结肠上皮层。糖原合成酶激酶3 β (GSK3 β)抑制剂的使用已被证明可以通过减少促炎反应有效地减轻UC啮齿动物模型的疾病症状。这些抑制剂是否通过刺激结肠上皮细胞增殖来促进结肠再生尚不清楚。我们研究了GSK3 β抑制剂氯化锂（LiCl）在小鼠急性dss诱导结肠炎恢复期是否能促进结肠再生和改善疾病症状。我们还测试了c-MYC转录因子（MYC）是否参与了这种反应。采用2.5%右旋糖酐硫酸钠（DSS）诱导野生型C57BL/6小鼠急性结肠炎5 d。在恢复期，小鼠每天腹腔注射LiCl或1X PBS作为对照。称重小鼠，测量结肠长度，评估疾病活动指数（DAI）评分，并对结肠切片进行组织学分析。我们分析了结肠上皮纯化制剂中的转录本和蛋白质。我们通过IP注射给药MYC抑制剂10058-F4来评估MYC在结肠再生中的作用。锂治疗通过增加Myc转录物、Myc蛋白的表达以及结肠上皮中Wnt/ Myc靶基因亚群的表达，促进了急性dss诱导损伤的恢复。10058-F4抑制MYC功能使锂反应减弱。通过诱导Myc在结肠上皮中的表达，锂促进dss诱导结肠炎后的结肠再生。因此，使用锂可能对UC患者有治疗价值。
Chronic inflammation disrupts the colonic epithelial layer in patients afflicted by ulcerative colitis (UC). The use of inhibitors of glycogen synthase kinase three beta (GSK3 beta) has proven efficacious to mitigate disease symptoms in rodent models of UC by reducing the pro-inflammatory response. Less is known about whether these inhibitors promote colonic regeneration by stimulating proliferation of colonic epithelial cells.We investigated whether delivery of the GSK3 beta inhibitor, lithium chloride (LiCl), during the recovery period from acute DSS-induced colitis in mice promoted colonic regeneration and ameliorated disease symptoms. We also tested whether the c-MYC transcription factor (MYC) was involved in this response.Acute colitis was induced by administration of 2.5 % dextran sodium sulfate (DSS) to wild-type C57BL/6 mice for 5 days. During the recovery period, mice received a daily intraperitoneal (IP) injection of LiCl or 1X PBS as a control. Mice were weighed, colon lengths measured, disease activity index (DAI) scores were assessed, and histological analyses were performed on colonic sections. We analyzed transcripts and proteins in purified preparations of the colonic epithelium. We delivered the MYC inhibitor 10058-F4 via IP injection to assess the role of MYC in colonic regeneration.Lithium treatments promoted recovery from acute DSS-induced damage by increasing expression of Myc transcripts, MYC proteins, and expression of a subset of Wnt/MYC target genes in the colonic epithelium. Inhibiting MYC function with 10058-F4 blunted the lithium response.By inducing Myc expression in the colonic epithelium, lithium promotes colonic regeneration after DSS-induced colitis. Therefore, the use of lithium may be of therapeutic value to manage individuals afflicted by UC.