Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis.
Therapeutic Potential of a Small-Molecule STAT3 Inhibitor in a Mouse Model of Colitis.
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作者：
我们使用临床前研究中广泛使用的右旋糖酐硫酸钠 (DSS) 小鼠结肠炎模型来确定 STAT3 对 IBD 的影响。 STAT3 有两种亚型：（STAT3α；具有促炎和抗凋亡功能；STAT3β；可减弱 STAT3α 的作用）。在当前的研究中，我们通过检查仅表达 STAT3α 的小鼠和接受 TTI-101（两种 STAT3 亚型的直接小分子抑制剂）治疗的小鼠中 DSS 诱导的结肠炎，确定了 STAT3 在所有组织中对 IBD 的影响。我们证明，与野生型小鼠相比，仅表达 STAT3α 的小鼠中 DSS 诱导的结肠炎更为严重，并且 TTI-101 的给药完全预防了 DSS 诱导的结肠炎，并逆转了 CRC 相关基因的上调。背景和目的：炎症性肠病（IBD）易患结直肠癌（CRC）。在目前的研究中，我们使用临床前研究中广泛使用的葡聚糖硫酸钠（DSS）小鼠结肠炎模型来确定STAT3对IBD的贡献。 STAT3 有两种亚型：（STAT3 α；具有促炎和抗凋亡功能；STAT3β；可减弱 STAT3α 的作用）。在当前的研究中，我们通过检查仅表达 STAT3α 的小鼠和接受 TTI-101（两种 STAT3 亚型的直接小分子抑制剂）治疗的小鼠中 DSS 诱导的结肠炎，确定了 STAT3 在所有组织中对 IBD 的影响。方法：我们对转基因 STAT3α 敲入（STAT3β 缺陷；ΔβΔβ）小鼠和野生型 (WT) 同窝笼对照小鼠给予 DSS (5%) 7 天后，检查了死亡率、体重减轻、直肠出血、腹泻、结肠缩短、结肠 CD4+ T 细胞凋亡以及产生 IL-17 细胞的结肠浸润。我们还在 WT 小鼠中研究了 TTI-101 对 DSS 诱导的结肠炎这些终点的影响。结果：与笼对照野生型小鼠相比，ΔβΔβ转基因小鼠所检查的 DSS 诱导结肠炎的每种临床表现均加剧。重要的是，用 TTI-101 治疗 DSS 给药的 WT 小鼠可完全减弱每种临床表现，并导致结肠 CD4+ T 细胞凋亡增加，IL-17 产生细胞的结肠浸润减少，以及与炎症、细胞凋亡抗性和结直肠癌转移相关的 STAT3 上调基因的结肠 mRNA 水平下调。结论：因此，小分子靶向 STAT3 可能有益于治疗 IBD 和预防 IBD 相关结直肠癌。
We used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3. We demonstrated that DSS-induced colitis is more severe in mice that express only STAT3α compared to wild-type mice and that administration of TTI-101 completely prevented DSS-induced colitis as well as reversed upregulation of CRC-associated genes. Background and Aims: Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC). In the current studies, we used the dextran sodium sulfate (DSS) murine model of colitis, which is widely used in preclinical studies, to determine the contribution of STAT3 to IBD. STAT3 has two isoforms: (STAT3 α; which has pro-inflammatory and anti-apoptotic functions, and STAT3β; which attenuates the effects of STAT3α). In the current study, we determined the contribution of STAT3 to IBD across all tissues by examining DSS-induced colitis in mice that express only STAT3α and in mice treated with TTI-101, a direct small-molecule inhibitor of both isoforms of STAT3. Methods: We examined mortality, weight loss, rectal bleeding, diarrhea, colon shortening, apoptosis of colonic CD4+ T-cells, and colon infiltration with IL-17-producing cells following 7-day administration of DSS (5%) to transgenic STAT3α knock-in (STAT3β-deficient; ΔβΔβ) mice and wild-type (WT) littermate cage control mice. We also examined the effect of TTI-101 on these endpoints in DSS-induced colitis in WT mice. Results: Each of the clinical manifestations of DSS-induced colitis examined was exacerbated in ΔβΔβ transgenic versus cage-control WT mice. Importantly, TTI-101 treatment of DSS-administered WT mice led to complete attenuation of each of the clinical manifestations and also led to increased apoptosis of colonic CD4+ T cells, reduced colon infiltration with IL-17-producing cells, and down-modulation of colon mRNA levels of STAT3-upregulated genes involved in inflammation, apoptosis resistance, and colorectal cancer metastases. Conclusions: Thus, small-molecule targeting of STAT3 may be of benefit in treating IBD and preventing IBD-associated colorectal cancer.
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影响因子：
11.5
作者：
Kettner, Nicole M.;Vijayaraghavan, Smruthi;Keyomarsi, Khandan
通讯作者：
Keyomarsi, Khandan
影响因子：
10.5
作者：
Chapman, RS;Lourenco, PC;Watson, CJ
通讯作者：
Watson, CJ
DOI：
10.1016/j.lungcan.2015.09.014
发表时间：
2015-11
期刊：
Lung cancer (Amsterdam, Netherlands)
影响因子：
--
作者：
Lewis KM;Bharadwaj U;Eckols TK;Kolosov M;Kasembeli MM;Fridley C;Siller R;Tweardy DJ
通讯作者：
Tweardy DJ
影响因子：
50.3
作者：
Calon A;Espinet E;Palomo-Ponce S;Tauriello DV;Iglesias M;Céspedes MV;Sevillano M;Nadal C;Jung P;Zhang XH;Byrom D;Riera A;Rossell D;Mangues R;Massagué J;Sancho E;Batlle E
通讯作者：
Batlle E
影响因子：
3.4
作者：
Ji, Hong;Greening, David W.;Simpson, Richard J.
通讯作者：
Simpson, Richard J.