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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Substance P mediates antiapoptotic responses in human colonocytes by Akt activation
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Substance P mediates antiapoptotic responses in human colonocytes by Akt activation

机译：P物质通过Akt激活介导人结肠细胞的抗凋亡反应

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摘要

We examined the hypothesis that substance P (SP) and the neurokinin-1 receptor (NK-1R), both in vitro and in vivo, promote mucosal healing during recovery from colitis by stimulating antiapoptotic pathways in human colonic epithelial cells. For the in vitro experiments, human nontransformed NCM460 colonocytes stably transfected with NK-1R (NCM460-NK-1R cells) were exposed to SP, and cell viability assays, TUNEL assays, and Western blot analyses were used to detect apoptotic and antiapoptotic pathways. SP exposure of NCM460-NK-1R colonocytes stimulated phosphoryla-tion of the antiapoptotic molecule Akt and inhibited tamoxifen-induced cell death and apoptosis evaluated by the cell viability assay and poly(ADP-ribose) polymerase cleavage, respectively. SP-induced phosphorylation of Akt and cleavage of poly(ADP-ribose) polymerase were inhibited by blockade of integrin αVβ3, Jak2, and activation of phosphatidylinositol 3-kinase. For the in vivo experiments, C57BL/6 mice, administered 5% dextran sulfate (DSS) dissolved in tap water for 5 days followed by a 5-day recovery period, were treated with the NK-1R antagonist CJ-12,255 or vehicle. Vehicle-treated mice showed increased colonic Akt phosphorylation and apoptosis compared with mice that received no DSS. In contrast, daily i.p. administration of CJ-12,255 for 5 days post-DSS suppressed Akt activation, exacerbated colitis, and enhanced apoptosis, and pharmacologic inhibition of Akt, either alone or together with CJ-12,255, produced a similar effect. Thus, SP, through NK-1R, possesses antiapoptotic effects in the colonic mucosa by activating Akt, which prevents apoptosis and mediates tissue recovery during colitis.
机译：我们检查了以下假设：物质P（SP）和神经激肽1受体（NK-1R）在体外和体内均通过刺激人类结肠上皮细胞的抗凋亡途径而从结肠炎恢复过程中促进粘膜愈合。对于体外实验，将用NK-1R稳定转染的人非转化NCM460结肠细胞（NCM460-NK-1R细胞）暴露于SP，并使用细胞活力测定，TUNEL测定和Western印迹分析来检测凋亡和抗凋亡途径。 SP暴露于NCM460-NK-1R结肠细胞可刺激抗凋亡分子Akt磷酸化，并抑制他莫昔芬诱导的细胞死亡和凋亡，分别通过细胞活力测定和聚（ADP-核糖）聚合酶裂解来评估。 SP诱导的Akt磷酸化和聚（ADP-核糖）聚合酶的裂解被整联蛋白αVβ3，Jak2的阻断和磷脂酰肌醇3-激酶的激活所抑制。对于体内实验，用NK-1R拮抗剂CJ-12,255或赋形剂处理C57BL / 6小鼠，将其溶于自来水中的5％硫酸葡聚糖（DSS）给药5天，然后恢复5天。与未接受DSS的小鼠相比，经媒介物处理的小鼠显示出增加的结肠Akt磷酸化和细胞凋亡。相反，每日i.p. DSS后5天给予CJ-12,255抑制了Akt活化，加剧了结肠炎，并增强了细胞凋亡，单独或与CJ-12,255一起对Akt进行药理抑制，产生了相似的效果。因此，SP通过NK-1R通过激活Akt在结肠粘膜中具有抗凋亡作用，从而防止细胞凋亡并介导结肠炎期间的组织恢复。

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