Deng Qi, Zhang Jiaojiao, Gao Yaqun, She Xiaofei, Wang Yunchao, Wang Yilin, Ge Xin
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University500 Dongchuan Road, Shanghai 200241, China.
Bio-X Institutes, Key Laboratory for The Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiaotong UniversityShanghai 200240, China.
Am J Transl Res. 2017 Apr 15;9(4):1810-1821. eCollection 2017.
Pulmonary fibrosis is a complex pathological process characterized by massive destruction of the structure of lung tissues and aggravated pulmonary function impairment. The underlying mechanisms of pulmonary fibrosis are incompletely understood and therefore limited treatment options are available currently. Here, we report that MLN4924, an NEDD8 activation enzyme (NAE) activity-inhibiting molecule, blocks the maintenance and progression of established pulmonary fibrosis. We found that MLN4924 acts against bleomycin-induced pulmonary fibrosis mainly at the early inflammatory stage. Pharmacologically targeting the neddylation of Cullin-Ring E3 ligase (CRL) by MLN4924, significantly abrogated NF-κB responses, suppressed MAPK activity, and reduced secretion of TNF-α-elicited pro-inflammatory cytokines and MCP1-induced chemokines. MLN4924 inhibited pro-inflammatory responses while maintaining or increasing the production of the anti-inflammatory mediators such as anti-inflammatory interleukins (ILs) following bleomycin administration, which is closely correlated to its blocking NF-κB-mediated signaling. Consistently, our studies identified MLN4924 as a promising therapeutic drug for pulmonary fibrosis and suggested a potential role of MLN4924 that fine tunes the MAPK signaling pathway controlling the inflammatory reactions at the early stages of pulmonary fibrosis. In addition, our findings may broaden the potential practical application of MLN4924 as an effective therapeutic strategy against other inflammation-associated diseases.
肺纤维化是一种复杂的病理过程，其特征是肺组织结构大量破坏，肺功能损害加重。肺纤维化的潜在机制尚未完全明确，因此目前可用的治疗选择有限。在此，我们报告MLN4924，一种抑制NEDD8激活酶（NAE）活性的分子，可阻止已形成的肺纤维化的维持和进展。我们发现MLN4924主要在早期炎症阶段对抗博来霉素诱导的肺纤维化。MLN4924通过药理学方法靶向Cullin-Ring E3连接酶（CRL）的NEDD化，显著消除了NF-κB反应，抑制了MAPK活性，并减少了TNF-α诱导的促炎细胞因子和MCP1诱导的趋化因子的分泌。在给予博来霉素后，MLN4924抑制促炎反应，同时维持或增加抗炎介质如抗炎白细胞介素（ILs）的产生，这与其阻断NF-κB介导的信号密切相关。一致地，我们的研究确定MLN4924是一种有前景的肺纤维化治疗药物，并表明MLN4924在肺纤维化早期微调控制炎症反应的MAPK信号通路中具有潜在作用。此外，我们的发现可能拓宽MLN4924作为针对其他炎症相关疾病的有效治疗策略的潜在实际应用。
