Department of Molecular and Translational Medicine, University of Brescia, Italy.
Chiesi Farmaceutici S.p.A., Corporate Pre-Clinical R&D, Largo F. Belloli 11/A, Parma 43122, Italy.
Biochem Pharmacol. 2019 May;163:371-380. doi: 10.1016/j.bcp.2019.03.006. Epub 2019 Mar 6.
Phosphodiesterase 4 (PDE4) inhibitors are used to treat autoimmune and inflammatory diseases, such as psoriasis and chronic obstructive pulmonary disease (COPD). CHF6001 is a novel, potent and selective inhaled PDE4 inhibitor in development for the treatment of COPD. When tested in vitro on human dendritic cells (DCs), CHF6001 decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CXCL8, CCL3, CXCL10 and CCL19) and of Th1- and Th17-polarizing cytokines (IL-12, IL-23 and IL-1β). In contrast to β-methasone, a reference steroid anti-inflammatory drug, CHF6001 increased the secretion of CCL22, a Th2 recruiting chemokine, and the expression of the lymph node homing receptor CCR7. Accordingly, the migration of DCs to CCR7 ligands was increased, while migration to pro-inflammatory chemokines was decreased. Of note, the action of CHF6001 was apparently mediated by a promoter-specific decrease in NF-κB p65 recruitment, independent of perturbation of LPS signalling or NF-κB nuclear translocation. Our results indicate that CHF6001 can modulate DC pro-inflammatory Th1/Th17 polarizing potential by fine tuning the transcriptional activity of the master inflammatory transcription factor NF-κB. Therefore, CHF6001 may prove useful to control Th1/Th17-polarized inflammatory diseases such as COPD.
磷酸二酯酶 4（PDE4）抑制剂被用于治疗自身免疫性和炎症性疾病，如银屑病和慢性阻塞性肺疾病（COPD）。CHF6001 是一种新型、强效和选择性的吸入性 PDE4 抑制剂，正在开发用于治疗 COPD。在体外对人树突状细胞（DCs）进行测试时，CHF6001 降低了促炎细胞因子（TNF-α 和 IL-6）、趋化因子（CXCL8、CCL3、CXCL10 和 CCL19）以及 Th1 和 Th17 极化细胞因子（IL-12、IL-23 和 IL-1β）的释放。与参考的类固醇抗炎药物β-甲泼尼龙不同，CHF6001 增加了 Th2 募集趋化因子 CCL22 的分泌和淋巴结归巢受体 CCR7 的表达。因此，DC 向 CCR7 配体的迁移增加，而向促炎趋化因子的迁移减少。值得注意的是，CHF6001 的作用显然是通过 NF-κB p65 募集的启动子特异性减少介导的，而不干扰 LPS 信号或 NF-κB 核易位。我们的研究结果表明，CHF6001 可以通过精细调节主炎症转录因子 NF-κB 的转录活性来调节 DC 的促炎 Th1/Th17 极化潜能。因此，CHF6001 可能有助于控制 COPD 等 Th1/Th17 极化炎症性疾病。
