IAPs and RIPK1 mediate LPS-induced cytokine production in healthy subjects and Crohn's disease.

IF 3.4 3区 医学 Q3 IMMUNOLOGY Clinical and experimental immunology Pub Date : 2024-02-19 DOI:10.1093/cei/uxad092
Jakob Benedict Seidelin, Simone Jensen, Morten Hansen, Mariana Rodrigues de Carvalho Bronze, Delphine Cuchet-Lourenҫo, Sergey Nejentsev, Eric Charles LaCasse, Ole Haagen Nielsen
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Abstract

Innate immune activity fuels intestinal inflammation in Crohn's disease (CD), an inflammatory bowel disease. Identification and targeting of new molecular regulators of the innate activity are warranted to control the disease. Inhibitor of apoptosis proteins (IAPs) regulate both cell survival and inflammatory signaling. We investigated the effects of IAP inhibition by second mitochondria-derived activator of caspases (SMAC) mimetics (SMs) on innate responses and cell death to pathogen-associated molecular patterns in peripheral blood mononuclear cells (PBMCs) and monocytes. IAPs inhibited lipopolysaccharide (LPS)-induced expression of proinflammatory interleukin (IL)-1β, IL-6. Likewise, LPS (but not muramyl dipeptide or Escherichia coli) induced TNF-α was inhibited in CD and control PBMCs. The SM effect was partially reversed by inhibition of receptor-interacting serine/threonine-protein kinase 1 (RIPK1). The effect was mainly cell death independent. Thus, IAP inhibition by SMs leads to reduced production of proinflammatory cytokines and may be considered in the efforts to develop new therapeutic strategies to control CD.

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IAPs 和 RIPK1 在健康人和克罗恩病患者中介导 LPS 诱导的细胞因子产生。
在克罗恩病(CD)这种炎症性肠病中,先天性免疫活动助长了肠道炎症。为了控制这种疾病,有必要确定和瞄准先天性免疫活动的新分子调控因子。细胞凋亡抑制蛋白(IAPs)同时调节细胞存活和炎症信号转导。我们研究了线粒体衍生的第二种活化酶(SMAC)模拟物(SMs)抑制 IAP 对外周血单核细胞(PBMCs)和单核细胞对病原体相关分子模式的先天性反应和细胞死亡的影响。IAPs 可抑制脂多糖(LPS)诱导的促炎性白细胞介素(IL)-1β、IL-6 的表达。同样,CD 和对照组 PBMCs 也能抑制 LPS(但不能抑制氨酰二肽或大肠杆菌)诱导的 TNF-α。抑制受体丝氨酸/苏氨酸蛋白激酶 1(RIPK1)可部分逆转 SM 的效应。这种效应主要与细胞死亡无关。因此,SM抑制IAP可减少促炎细胞因子的产生,在开发控制CD的新治疗策略时可加以考虑。
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来源期刊
CiteScore
8.40
自引率
2.20%
发文量
101
审稿时长
3-8 weeks
期刊介绍: Clinical & Experimental Immunology (established in 1966) is an authoritative international journal publishing high-quality research studies in translational and clinical immunology that have the potential to transform our understanding of the immunopathology of human disease and/or change clinical practice. The journal is focused on translational and clinical immunology and is among the foremost journals in this field, attracting high-quality papers from across the world. Translation is viewed as a process of applying ideas, insights and discoveries generated through scientific studies to the treatment, prevention or diagnosis of human disease. Clinical immunology has evolved as a field to encompass the application of state-of-the-art technologies such as next-generation sequencing, metagenomics and high-dimensional phenotyping to understand mechanisms that govern the outcomes of clinical trials.
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