Abstract:
Inflammation and lipid regulator with UBA-like and NBR1-like domains (ILRUN) is a protein-encoding gene associated with innate immune signaling, lipid metabolism and cancer. In the context of innate immunity, ILRUN inhibits IRF3-mediated transcription of antimicrobial and proinflammatory cytokines by inducing degradation of the transcriptional coactivators CBP and p300. There remains a paucity of information, however, regarding the innate immune roles of ILRUN beyond in vitro analyses. To address this, we utilize a knockout mouse model to investigate the effect of ILRUN on cytokine expression in splenocytes and on the development of immune cell populations in the spleen and thymus. We show elevated production of tumor necrosis factor and interleukin-6 cytokines in ILRUN-deficient splenocytes following stimulation with the innate immune ligands polyinosinic:polycytidylic acid or lipopolysaccharide. Differences were also observed in the populations of several T cell subsets, including regulatory, mucosal-associated invariant and natural killer. These data identify novel functions for ILRUN in the development of certain immune cell populations and support previous in vitro findings that ILRUN negatively regulates the synthesis of pathogen-stimulated cytokines. This establishes the ILRUN knockout mouse model as a valuable resource for further study of the functions of ILRUN in health and disease.
摘要:
具有UBA样和NBR1样结构域(ILRUN)的炎症和脂质调节剂是与先天免疫信号相关的蛋白质编码基因,脂质代谢和癌症。在先天免疫的背景下,ILRUN通过诱导转录共激活因子CBP和p300的降解来抑制抗微生物和促炎细胞因子的IRF3介导的转录。仍然缺乏信息,然而,关于ILRUN超越体外分析的先天免疫作用。为了解决这个问题,我们利用基因敲除小鼠模型来研究ILRUN对脾细胞中细胞因子表达以及对脾和胸腺中免疫细胞群发育的影响。我们显示,在用先天性免疫配体聚肌苷酸:聚胞苷酸或脂多糖刺激后,ILRUN缺陷的脾细胞中肿瘤坏死因子和白介素6细胞因子的产生增加。在几个T细胞亚群的群体中也观察到差异,包括监管,粘膜相关的不变和自然杀伤。这些数据鉴定了ILRUN在某些免疫细胞群体的发育中的新功能,并且支持先前的体外发现,即ILRUN负调节病原体刺激的细胞因子的合成。这将ILRUN敲除小鼠模型确立为进一步研究ILRUN在健康和疾病中的功能的有价值的资源。