A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production
A RIPK2 inhibitor delays NOD signalling events yet prevents inflammatory cytokine production
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DOI：
10.1038/ncomms7442
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发表时间：
2015-03-01
影响因子：
16.6
通讯作者：
Silke, John
中科院分区：
文献类型：
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作者：
Nachbur, Ueli;Stafford, Che A.;Silke, John
细胞内核苷酸结合和寡聚化结构域(NOD)受体识别包括细菌肽多糖在内的抗原，并通过激活核因子-kappaB和MAP激活酶来触发促炎细胞因子的产生来启动免疫反应。受体相互作用蛋白激酶2(RIPK2)在NOD介导的核因子-kappaB的激活和细胞因子的产生中起关键作用。在这里，我们开发并鉴定了一种选择性的RIPK2激酶抑制剂WEHI-345，它可以延迟Nod参与下游的RIPK2泛素化和核因子-kappa B的激活。尽管WEHI-345只延迟了NOD刺激下的核因子-kappa B的激活，但它在体外和体内都阻止了细胞因子的产生，并改善了小鼠的实验性自身免疫性脑脊髓炎。我们的研究强调了RIPK2的激酶活性对适当的免疫反应的重要性，并证明了抑制RIPK2在NOD驱动的炎症性疾病中的治疗潜力。
Intracellular nucleotide binding and oligomerization domain (NOD) receptors recognize antigens including bacterial peptidoglycans and initiate immune responses by triggering the production of pro-inflammatory cytokines through activating NF-kappa B and MAP kinases. Receptor interacting protein kinase 2 (RIPK2) is critical for NOD-mediated NF-kappa B activation and cytokine production. Here we develop and characterize a selective RIPK2 kinase inhibitor, WEHI-345, which delays RIPK2 ubiquitylation and NF-kappa B activation downstream of NOD engagement. Despite only delaying NF-kappa B activation on NOD stimulation, WEHI-345 prevents cytokine production in vitro and in vivo and ameliorates experimental autoimmune encephalomyelitis in mice. Our study highlights the importance of the kinase activity of RIPK2 for proper immune responses and demonstrates the therapeutic potential of inhibiting RIPK2 in NOD-driven inflammatory diseases.