Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease.
Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease.
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DOI：
10.1038/nm.4307
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发表时间：
2017-05
期刊：
影响因子：
82.9
通讯作者：
Powrie F
中科院分区：
文献类型：
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作者：
West NR;Hegazy AN;Owens BMJ;Bullers SJ;Linggi B;Buonocore S;Coccia M;Görtz D;This S;Stockenhuber K;Pott J;Friedrich M;Ryzhakov G;Baribaud F;Brodmerkel C;Cieluch C;Rahman N;Müller-Newen G;Owens RJ;Kühl AA;Maloy KJ;Plevy SE;Oxford IBD Cohort Investigators;Keshav S;Travis SPL;Powrie F
炎症性肠病（IBD），包括克罗恩病（CD）和溃疡性结肠炎（UC），是由扰动的细胞因子途径驱动的胃肠道的复杂慢性炎症性病症。抗肿瘤坏死因子-α（TNF）抗体是IBD的主要治疗方法。然而，高达40%的患者对抗TNF药物无反应，因此确定替代治疗靶点是当务之急。在这里，我们表明，与健康对照组相比，炎症性肠病患者炎症肠道中细胞因子抑瘤素M（OSM）及其受体（OSMR）的表达增加，并与组织病理学疾病的严重程度密切相关。OSMR在非造血、非上皮肠基质细胞中表达，其通过产生各种促炎分子（包括白细胞介素-6（IL-6）、白细胞粘附因子ICAM-1和吸引嗜中性粒细胞、单核细胞和T细胞的趋化因子）来响应OSM。在抗TNF抗性肠道炎症的动物模型中，OSM的遗传缺失或药理学阻断显著减弱结肠炎。此外，基于对超过200例IBD患者的分析，包括来自英夫利西单抗和戈利木单抗的3期临床试验的两个队列，治疗前高OSM表达与抗TNF治疗失败密切相关。因此，OSM是IBD的潜在生物标志物和治疗靶点，与抗TNF耐药患者特别相关。
Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are a mainstay therapeutic approach for IBD. However, up to 40% of patients are non-responsive to anti-TNF agents, and identifying alternative therapeutic targets is a priority. Here we show that expression of the cytokine Oncostatin M (OSM) and its receptor (OSMR) is increased in the inflamed intestine of IBD patients compared to healthy controls, and correlates closely with histopathological disease severity. OSMR is expressed in non-hematopoietic, non-epithelial intestinal stromal cells, which respond to OSM by producing various pro-inflammatory molecules including interleukin-6 (IL-6), the leukocyte adhesion factor ICAM-1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, high pre-treatment OSM expression is strongly associated with failure of anti-TNF therapy based on analysis of over 200 IBD patients, including two cohorts from phase 3 clinical trials of infliximab and golimumab. OSM is thus a potential biomarker and therapeutic target for IBD, with particular relevance for anti-TNF resistant patients.