Cell Biology and Disease Research Group, Cancer Research Institute, University of South Australia, Adelaide, SA 5000, Australia.
Centre for Drug Discovery and Development, Cancer Research Institute, University of South Australia, Adelaide, SA 5000, Australia.
Cells. 2020 Feb 5;9(2):372. doi: 10.3390/cells9020372.
Innate immunity is critical for host defence against pathogen and environmental challenge and this involves the production and secretion of immune mediators, such as antimicrobial peptides and pro-inflammatory cytokines. However, when dysregulated, innate immunity can contribute to multifactorial diseases, including inflammatory rheumatic disorders, type 2 diabetes, cancer, neurodegenerative and cardiovascular diseases and even septic shock. During an innate immune response, antimicrobial peptides and cytokines are trafficked via Rab11 multivesicular endosomes, and then sorted into Rab11 vesicles for traffic to the plasma membrane and secretion. In this study, a cyclin-dependent kinase inhibitor CDKI-73 was used to determine its effect on the innate immune response, based on previously identified targets for this compound. Our results showed that CDKI-73 inhibited the delivery of Rab11 vesicles to the plasma membrane, resulting in the accumulation of large multivesicular Rab11 endosomes near the cell periphery. In addition to the effect on endosome delivery, CDKI-73 down-regulated the amount of innate immune cargo, including the antimicrobial peptide Drosomycin and pro-inflammatory cytokines interleukin-6 (IL-6) and tumour necrosis factor alpha (TNFα). We concluded that CDKI-73 has the potential to regulate the delivery and secretion of certain innate immune cargo, which could be used to control inflammation.
先天免疫对于宿主抵御病原体和环境挑战至关重要，这涉及到免疫介质的产生和分泌，如抗菌肽和促炎细胞因子。然而，当先天免疫失调时，它可能导致多种疾病，包括炎症性风湿性疾病、2 型糖尿病、癌症、神经退行性疾病和心血管疾病，甚至败血症性休克。在先天免疫反应中，抗菌肽和细胞因子通过 Rab11 多泡体被运输，然后被分拣到 Rab11 囊泡中，以便运输到质膜并分泌。在这项研究中，使用细胞周期蛋白依赖性激酶抑制剂 CDKI-73 来确定其对先天免疫反应的影响，这是基于该化合物先前确定的靶标。我们的结果表明，CDKI-73 抑制了 Rab11 囊泡向质膜的传递，导致大量多泡 Rab11 内体在细胞边缘附近积累。除了对内体传递的影响外，CDKI-73 还下调了先天免疫货物的数量，包括抗菌肽 Drosomycin 和促炎细胞因子白细胞介素 6 (IL-6) 和肿瘤坏死因子 alpha (TNFα)。我们得出结论，CDKI-73 有可能调节某些先天免疫货物的传递和分泌，这可用于控制炎症。
