期刊
NATURE MEDICINE
卷 23, 期 5, 页码 579-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4307
关键词
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资金
- NIHR Oxford Biomedical Research Centre [HBRWAE04 Task HB81.G]
- Irvington Institute (Cancer Research Institute)
- European Molecular Biology Organization (EMBO) [ALTF 116-2012]
- Marie Curie fellowship (FP7-PEOPLE-IEF) [330621]
- Ecole Normale Superieure of Lyon
- French Ministry of Education
- Medical Research Council [MR/K018779/1]
- Edward Penley Abraham Trust
- Wellcome Trust [102972]
- Wellcome Trust
- Foundation Louis Jeantet
- MRC [MR/K018779/1, MC_UU_00008/7, G0200231, MC_UU_12010/7] Funding Source: UKRI
- Academy of Medical Sciences (AMS) [AMS-SGCL7-Bird-Lieberman] Funding Source: researchfish
- Medical Research Council [MC_UU_00008/7, G0200231, MR/K018779/1, MC_UU_12010/7] Funding Source: researchfish
- National Institute for Health Research [NIHR-RP-R3-12-026, NF-SI-0515-10005] Funding Source: researchfish
- Wellcome Trust [109965/Z/15/Z, 102974/Z/13/Z] Funding Source: researchfish
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-alpha (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, 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, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.
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