Laselva Onofrio, Criscione Maria Laura, Allegretta Caterina, Di Gioia Sante, Liso Arcangelo, Conese Massimo
Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.
Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
Front Mol Biosci. 2022 Jul 12;9:905468. doi: 10.3389/fmolb.2022.905468. eCollection 2022.
Cystic Fibrosis (CF) patients are prone to contracting bacterial lung infections with opportunistic pathogens, especially . Prolonged infections have been linked to chronic inflammation in the CF lung, whose hallmarks are increased levels of cytokines (i.e., TNF-α, IL-1β, IL-6) and neutrophil attraction by chemokines, like IL-8. Recently, insulin-like growth factor binding protein 6 (IGFBP-6) has been shown to play a putative role in the immune system and was found at higher levels in the sera and synovial tissue of rheumatoid arthritis patients. Moreover, it has been demonstrated that IGFBP-6 has chemoattractant properties towards cells of the innate (neutrophils, monocytes) and adaptive (T cells) immunity. However, it is not known whether IGFBP-6 expression is dysregulated in airway epithelial cells under infection/inflammatory conditions. Therefore, we first measured the basal IGFBP-6 mRNA and protein levels in bronchial epithelial cells lines (Wt and F508del-CFTR CFBE), finding they both are upregulated in F508del-CFTR CFBE cells. Interestingly, LPS and IL-1β+TNFα treatments increased the IGFBP-6 mRNA level, that was reduced after treatment with an anti-inflammatory (Dimethyl Fumarate) in CFBE cell line and in patient-derived nasal epithelial cultures. Lastly, we demonstrated that IGFBP-6 reduced the level of pro-inflammatory cytokines in both CFBE and primary nasal epithelial cells, without affecting rescued CFTR expression and function. The addition of a neutralizing antibody to IGFBP-6 increased pro-inflammatory cytokines expression under challenge with LPS. Together, these data suggest that IGFBP-6 may play a direct role in the CF-associated inflammation.
囊性纤维化（CF）患者容易感染由机会性病原体引起的细菌性肺部感染，尤其是……长期感染与CF肺部的慢性炎症有关，其特征是细胞因子（即TNF-α、IL-1β、IL-6）水平升高以及趋化因子（如IL-8）对中性粒细胞的吸引。最近，胰岛素样生长因子结合蛋白6（IGFBP-6）已被证明在免疫系统中发挥假定作用，并且在类风湿性关节炎患者的血清和滑膜组织中发现其水平较高。此外，已经证明IGFBP-6对先天免疫细胞（中性粒细胞、单核细胞）和适应性免疫细胞（T细胞）具有趋化特性。然而，尚不清楚在感染/炎症条件下气道上皮细胞中IGFBP-6的表达是否失调。因此，我们首先测量了支气管上皮细胞系（野生型和F508del-CFTR CFBE）中基础IGFBP-6 mRNA和蛋白质水平，发现它们在F508del-CFTR CFBE细胞中均上调。有趣的是，LPS和IL-1β+TNFα处理增加了IGFBP-6 mRNA水平，在用抗炎药（富马酸二甲酯）处理后，CFBE细胞系和患者来源的鼻上皮培养物中的该水平降低。最后，我们证明IGFBP-6降低了CFBE和原代鼻上皮细胞中促炎细胞因子的水平，而不影响挽救的CFTR表达和功能。添加针对IGFBP-6的中和抗体可增加LPS刺激下促炎细胞因子的表达。总之，这些数据表明IGFBP-6可能在CF相关炎症中起直接作用。
