Triptolide induces suppressor of cytokine signaling-3 expression and promotes lamina propria mononuclear cells apoptosis in Crohn's colitis
Triptolide induces suppressor of cytokine signaling-3 expression and promotes lamina propria mononuclear cells apoptosis in Crohn's colitis
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DOI：
10.1016/j.intimp.2013.04.018
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发表时间：
2013-06-01
影响因子：
5.6
通讯作者：
Li, Jieshou
中科院分区：
文献类型：
--
作者：
Li, Yi;Tian, Yun;Li, Jieshou
背景：IL-6/STAT3/SOCS3信号通路通过在固有层单核细胞（LPMCs）中诱导抗凋亡因子Bcl-2和Bcl-xl在克罗恩病的发病过程中发挥重要作用。我们之前报道过雷公藤甲素通过抑制IL-6反式信号传导的机制在小鼠结肠炎中显示出治疗活性。用IL-10基因缺陷的结肠炎小鼠进行雷公藤甲素给药实验。方法：本研究进一步探讨雷公藤甲素减轻克罗恩结肠炎的作用机制。采用IL-10基因缺陷小鼠(IL-10（-)/(-)）进行慢性雷公藤甲素给药实验。流式细胞术检测固有层单个核细胞凋亡情况。Western blot检测SOCS、Bcl-2、Bcl-xl和Bax。此外，我们还利用体外培养的乳糜泻患者的肠道来观察雷公藤甲素的直接作用。结果：雷公藤甲素促进lpmc细胞凋亡。有趣的是，雷公藤甲素显著诱导了lp - cd4阳性细胞的凋亡，而lp - cd4阴性细胞的凋亡则没有。雷公藤甲素显著诱导lpmc中SOCS3蛋白表达，降低STAT3靶向抗凋亡基因Bcl-2和Bcl-xl。用雷公藤甲素培养的结肠外植体的体外研究证实了这一结果。结论：本研究结果表明雷公藤甲素治疗可恢复肠道内LP-T细胞凋亡的稳态平衡，并通过调节IL-6/STAT3/SOCS3信号通路介导雷公藤甲素治疗的新作用机制。(c) 2013 Elsevier B.V.版权所有
Background: IL-6/STAT3/SOCS3 signaling pathway plays an important role in the pathogenesis of Crohn's disease by induction of the antiapoptotic factors Bcl-2 and Bcl-xl in lamina propria mononuclear cells (LPMCs). We previously reported that triptolide showed therapeutic activity in mouse colitis by mechanisms involving suppression of IL-6 trans-signaling. IL-10 gene-deficient mice with established colitis were used for the experiments with triptolide administration.Methods: This study further investigates the mechanism by which triptolide attenuates Crohn's colitis. IL-10 gene-deficient mice (IL-10(-)/(-)) of 10-12 weeks with established colitis were used for the experiments with chronic triptolide administration. Apoptosis of lamina propria mononuclear cells (LPMCs) were measured by flow cytometry. SOCS, Bcl-2, Bcl-xl and Bax were determined by Western blot. Furthermore, an in vitro study was performed by using cultured intestine from CD patients to observe the direct effects of triptolide.Results: Our data indicated triptolide promoted apoptosis in LPMCs in vivo. Interestingly, triptolide significantly induced the apoptosis of LP-CD4-positive but not LP-CD4-negative cells. Triptolide significantly induced SOCS3 protein and reduced STAT3 target anti-apoptotic genes Bcl-2 and Bcl-xl in LPMCs. The results were confirmed by an in vitro study using colonic explants cultured with triptolide.Conclusions: Our results indicated that triptolide therapy may restore the homeostatic balance of LP-T cell apoptosis within the gut, and demonstrate a novel mechanism of action of triptolide therapy mediated through regulation IL-6/STAT3/SOCS3 signaling pathway. (c) 2013 Elsevier B.V. All rights reserved.