Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease.
Epithelial TNF Receptor Signaling Promotes Mucosal Repair in Inflammatory Bowel Disease.
复制标题
上皮TNF受体信号传导促进炎症性肠病的粘膜修复。
DOI：
10.4049/jimmunol.1601066
复制
发表时间：
2017-09-01
期刊：
影响因子：
--
通讯作者：
Barrett TA
中科院分区：
文献类型：
--
作者：
Bradford EM;Ryu SH;Singh AP;Lee G;Goretsky T;Sinh P;Williams DB;Cloud AL;Gounaris E;Patel V;Lamping OF;Lynch EB;Moyer MP;De Plaen IG;Shealy DJ;Yang GY;Barrett TA
嵌合抗 TNF 单克隆抗体对克罗恩病 (CD) 患者产生的显着治疗反应证明了 TNF 在炎症性肠病 (IBD) 中发挥着不可或缺的作用。然而，用依那西普（一种结合可溶性 TNF 的诱饵受体）治疗 CD 患者并不能改善疾病。为了探讨这种差异，我们在 CD 患者、人类细胞和临床前小鼠模型中探讨了 TNF 信号传导对 Wnt/β-连环蛋白介导的肠干细胞和祖细胞 (ISC/PC) 扩增的作用。我们假设 TNF 对肠上皮细胞 (IEC) 对损伤的反应发挥有益作用。在 CD 患者中，ISC/PC Wnt/β-连环蛋白信号传导与炎症状态相关。当用抗 CD3 mAb 刺激时，TNF 缺陷 (Tnf−/−) 小鼠表现出细胞凋亡增加、IEC 增殖减少和 Wnt 信号传导减少。骨髓嵌合体 (BMC) 小鼠揭示粘膜修复依赖于 BM 衍生细胞产生的 TNF 和抗辐射 IEC 表达的 TNFR。给予慢性 DSS 结肠炎的 WT-> Tnfr1/2−/− BMC 小鼠表现出溃疡愈合延迟、粘膜炎症增加和 Wnt/β-连环蛋白信号传导受损，这与上皮 TNFR 信号传导参与粘膜愈合的假设一致。通过对小鼠小肠和类结肠培养物中 TNF 诱导的 Wnt/β-连环蛋白靶基因表达以及在未转化的人 NCM460 细胞 (TOPFlash) 和小鼠 (TOP-GAL) 中 TNF 诱导的 β-连环蛋白激活的研究，证明了 TNF 对干细胞的直接影响。这些数据共同支持了以下假设：TNF 在 IBD 溃疡愈合过程中增强 Wnt/β-连环蛋白信号传导方面发挥有益作用。这些新发现将为临床医生和治疗化学家在努力为 IBD 患者开发新疗法时提供信息。
TNF plays an integral role in inflammatory bowel disease (IBD) as evidenced by the dramatic therapeutic responses in Crohn’s disease (CD) patients induced by chimeric anti-TNF mAbs. However, treatment of CD patients with etanercept, a decoy receptor that binds soluble TNF, fails to improve disease. To explore this discrepancy, we interrogated the role of TNF signaling on Wnt/β-catenin-mediated intestinal stem and progenitor cell (ISC/PC) expansion in CD patients, human cells, and preclinical mouse models. We hypothesized that TNF exerts beneficial effects on intestinal epithelial cell (IEC) responses to injury. In CD patients, ISC/PC Wnt/β-catenin signaling correlates with inflammation status. TNF-deficient (Tnf−/−) mice exhibited increased apoptosis, less IEC proliferation, and less Wnt signaling when stimulated with anti-CD3 mAb. Bone marrow chimera (BMC) mice revealed that mucosal repair depended on TNF production by BM-derived cells and TNFR expression by radioresistant IEC. WT-> Tnfr1/2−/− BMC mice given chronic DSS colitis exhibited delayed ulcer healing, more mucosal inflammation, and impaired Wnt/β-catenin signaling, consistent with the hypothesis that epithelial TNFR signaling participates in mucosal healing. The direct effect of TNF on stem cells was demonstrated by studies of TNF-induced Wnt/β-catenin target gene expression in murine enteroids and colonoid cultures and TNF-induced β-catenin activation in non-transformed human NCM460 cells (TOPFlash) and mice (TOP-GAL). Together these data support the hypothesis that TNF plays a beneficial role in enhancing Wnt/β-catenin signaling during ulcer healing in IBD. These novel findings will inform clinicians and therapeutic chemists alike as they strive to develop novel therapies for IBD patients.
登录
查看更多内容
影响因子：
64.5
作者：
Powell AE;Wang Y;Li Y;Poulin EJ;Means AL;Washington MK;Higginbotham JN;Juchheim A;Prasad N;Levy SE;Guo Y;Shyr Y;Aronow BJ;Haigis KM;Franklin JL;Coffey RJ
通讯作者：
Coffey RJ
影响因子：
4.4
作者：
Miura, N;Yamamoto, M;Hayakawa, S
通讯作者：
Hayakawa, S
影响因子：
24.5
作者：
Fujino, S;Andoh, A;Fujiyama, Y
通讯作者：
Fujiyama, Y
影响因子：
10.5
作者：
Pinto, D;Gregorieff, A;Clevers, H
通讯作者：
Clevers, H
影响因子：
29.4
作者：
Lee G;Goretsky T;Managlia E;Dirisina R;Singh AP;Brown JB;May R;Yang GY;Ragheb JW;Evers BM;Weber CR;Turner JR;He XC;Katzman RB;Li L;Barrett TA
通讯作者：
Barrett TA