Cyclin-dependent Kinase 9 as a Potential Target for Anti-TNF-resistant Inflammatory Bowel Disease.
Cyclin-dependent Kinase 9 as a Potential Target for Anti-TNF-resistant Inflammatory Bowel Disease.
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DOI：
10.1016/j.jcmgh.2022.05.011
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发表时间：
2022
影响因子：
7.2
通讯作者：
Lord, Graham M.
中科院分区：
文献类型：
--
作者：
Omer, Omer S.;Hertweck, Arnulf;Roberts, Luke B.;Lo, Jonathan W.;Clough, Jennie N.;Jackson, Ian;Pantazi, Eirini D.;Irving, Peter M.;MacDonald, Tom T.;Pavlidis, Polychronis;Jenner, Richard G.;Lord, Graham M.
对单一细胞因子阻断，即抗肿瘤坏死因子（TNF）治疗的抵抗，是炎症性肠病（IBD）患者日益关注的问题。转录因子T-bet是肠道内稳态的关键调节因子，与粘膜炎症有遗传联系，并控制多个基因的表达，如促炎细胞因子干扰素（IFN）-γ和TNF。因此，抑制T-bet可能为治疗IBD提供更有吸引力的前景，但在治疗靶向方面仍然具有挑战性。在这项研究中，我们评估了靶向的反式激活功能的T-bet使用抑制剂P-TEFb（CDK 9-细胞周期蛋白T），转录延伸因子下游的T-bet。使用适应性免疫介导的结肠炎模型，来自IBD患者的人结肠淋巴细胞和多个大型临床数据集，我们研究了细胞周期蛋白依赖性激酶9（CDK 9）抑制剂对结肠CD 4 + T细胞中细胞因子产生和基因表达的影响，并将这些遗传模块与IBD患者的临床反应联系起来。系统性CDK 9抑制导致免疫介导的结肠炎的组织学改善，并且与结肠CD 4 + T细胞衍生的IFN-γ和IL-17 A的靶向抑制相关。在IBD患者的结肠淋巴细胞中，CDK 9抑制剂有效地抑制了负责促炎信号传导的基因，特别是由T-bet调节的基因。值得注意的是，CDK 9抑制靶向在抗TNF抗性IBD中高度表达的基因，并且预测对抗TNF治疗无应答。总的来说，我们的研究结果表明CDK 9是抗TNF耐药IBD的潜在靶点，具有快速转化为临床的潜力。
Resistance to single cytokine blockade, namely anti-tumor necrosis factor (TNF) therapy, is a growing concern for patients with inflammatory bowel disease (IBD). The transcription factor T-bet is a critical regulator of intestinal homeostasis, is genetically linked to mucosal inflammation and controls the expression of multiples genes such as the pro-inflammatory cytokines interferon (IFN)-γ and TNF. Inhibiting T-bet may therefore offer a more attractive prospect for treating IBD but remains challenging to target therapeutically. In this study, we evaluate the effect of targeting the transactivation function of T-bet using inhibitors of P-TEFb (CDK9-cyclin T), a transcriptional elongation factor downstream of T-bet. Using an adaptive immune-mediated colitis model, human colonic lymphocytes from patients with IBD and multiple large clinical datasets, we investigate the effect of cyclin-dependent kinase 9 (CDK9) inhibitors on cytokine production and gene expression in colonic CD4+ T cells and link these genetic modules to clinical response in patients with IBD. Systemic CDK9 inhibition led to histological improvement of immune-mediated colitis and was associated with targeted suppression of colonic CD4+ T cell-derived IFN-γ and IL-17A. In colonic lymphocytes from patients with IBD, CDK9 inhibition potently repressed genes responsible for pro-inflammatory signalling, and in particular genes regulated by T-bet. Remarkably, CDK9 inhibition targeted genes that were highly expressed in anti-TNF resistant IBD and that predicted non-response to anti-TNF therapy. Collectively, our findings reveal CDK9 as a potential target for anti-TNF-resistant IBD, which has the potential for rapid translation to the clinic.
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影响因子：
3
作者：
Haining WN;Angelosanto J;Brosnahan K;Ross K;Hahn C;Russell K;Drury L;Norton S;Nadler L;Stegmaier K
通讯作者：
Stegmaier K
影响因子：
14.8
作者：
Olson CM;Jiang B;Erb MA;Liang Y;Doctor ZM;Zhang Z;Zhang T;Kwiatkowski N;Boukhali M;Green JL;Haas W;Nomanbhoy T;Fischer ES;Young RA;Bradner JE;Winter GE;Gray NS
通讯作者：
Gray NS
影响因子：
7.3
作者：
Bevington SL;Cauchy P;Withers DR;Lane PJ;Cockerill PN
通讯作者：
Cockerill PN
影响因子：
16.6
作者：
Haberman, Yael;Karns, Rebekah;Denson, Lee A.
通讯作者：
Denson, Lee A.
DOI：
10.1084/jem.20011956
发表时间：
2002-05-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Neurath MF;Weigmann B;Finotto S;Glickman J;Nieuwenhuis E;Iijima H;Mizoguchi A;Mizoguchi E;Mudter J;Galle PR;Bhan A;Autschbach F;Sullivan BM;Szabo SJ;Glimcher LH;Blumberg RS
通讯作者：
Blumberg RS