BC-1215是一种F-box only蛋白3（FBXO3）的抑制剂，具有抗炎作用。BC-1215抑制FBXO3-F-box和富含亮氨酸重复蛋白2（FBXL2）之间的相互作用，导致FBXL2表达上调，引起FBXL2介导的泛素化和肿瘤坏死因子受体（TNFR）相关因子6（TRAF6）或NOD-，LRR-和含pyrin域的蛋白3（NLRP3）的降解，随后导致炎性细胞因子产生下调。在本研究中，我们研究了BC-1215如何或是否抑制了LPS预处理的人类嗜酸性细胞样细胞系THP-1细胞中ATP诱导的IL-1β分泌问题。我们的结果表明，预处理BC-1215减弱了LPS预处理的THP-1细胞中ATP诱导的IL-1β分泌。采用BC-1215处理LPS预处理的THP-1细胞可以在蛋白质水平上降低NLRP3和pro-IL-1β的水平，但在mRNA水平上没有变化。此外，MG-132的处理可以抑制BC-1215诱导的NLRP3和pro-IL-1β蛋白的降解，并恢复它们的水平，表明BC-1215通过泛素蛋白酶体依赖性降解减少了NLRP3和pro-IL-1β的稳定性。我们的结果还表明，BC-1215增加的FBXL2与NLRP3和pro-IL-1β结合并泛素化，但不包括pro-caspase-1。这些结果表明，抑制FBXO3的BC-1215处理通过FBXL2介导的泛素化和降解pro-IL-1β以及NLRP3，抑制了LPS预处理的THP-1细胞中ATP诱导的IL-1β分泌，提示FBXO3是研发用于治疗炎症疾病的潜在治疗靶点。Copyright © 2023 Elsevier Inc. All rights reserved.

BC-1215, bis-pyridinyl benzyl ethanediamine, is an inhibitor of F-box only protein 3 (FBXO3) and exerts anti-inflammatory effects. BC-1215 inhibits interactions between FBXO3-F-box and the leucine rich repeat protein 2 (FBXL2), leading to the upregulation of FBXL2 expression, FBXL2-mediated ubiquitination and the degradation of tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) or NOD-, LRR- and the pyrin domain-containing protein 3 (NLRP3), which subsequently results in the down-regulation of inflammatory cytokine production. In the current study, we investigated the issue of whether or how BC-1215 suppresses the ATP-induced secretion of IL-1β in LPS-primed human macrophage-like cells, THP-1 cells. Our result show that pre-treatment with BC-1215 attenuated the ATP-induced secretion of IL-1β in LPS-primed THP-1 cells. Treatment of the LPS-primed THP-1 cells with BC-1215 resulted in a decrease in the level of NLRP3 and pro-IL-1β at the protein level, but not at the mRNA level. In addition, treatment with MG-132, but not leupeptin, inhibited the BC-1215-induced degradation of NLRP3 and pro-IL-1β proteins, and restored their levels, suggesting that BC-1215 decreases the stability of NLRP3 and pro-IL-1β at the protein level via proteasome-dependent degradation. Our results also show that FBXL2, which is increased by BC-1215, bound to and ubiquitinated NLRP3 and pro-IL-1β, but not pro-caspase-1. These collective results indicate that treatment with BC-1215, an inhibitor of FBXO3, inhibits ATP-induced IL-1β secretion via the FBXL2-mediated ubiquitination and degradation of pro-IL-1β as well as NLRP3 in LPS-primed THP-1 cells, suggesting that FBXO3 is a potential therapeutic target for developing agents against inflammatory diseases.Copyright © 2023 Elsevier Inc. All rights reserved.