Abstract:
The spontaneous migration of bone marrow neutrophils (BMNs) is typically induced by distant tumor cells during the early stage of the tumor and critically controls tumor progression and metastases. Therefore, identifying the key molecule that prevents this process is extremely important for suppressing tumors. Interleukin-37 (IL-37) can suppress pro-inflammatory cytokine generation via an IL-1R8- or Smad3-mediated pathway. Here, we demonstrate that human neutrophil IL-37 is responsively reduced by tumor cells and the recombinant IL-37 isoform d (IL-37d) significantly inhibits spontaneous BMN migration and tumor lesion formation in the lung by negatively modulating CCAAT/enhancer binding protein beta (C/EBPβ) in a Lewis lung carcinoma (LLC)-inducing lung cancer mouse model. Mechanistically, IL-37d promotes C/EBPβ ubiquitination degradation by facilitating ubiquitin ligase COP1 recruitment and disrupts C/EBPβ DNA binding abilities, thereby reducing neutrophil ATP generation and migration. Our work reveals an anti-tumor mechanism for IL-37 via destabilization of C/EBPβ to prevent spontaneous BMN migration and tumor progression.
摘要:
骨髓中性粒细胞(BMN)的自发迁移通常是在肿瘤的早期阶段由远处的肿瘤细胞诱导的,并且关键地控制肿瘤的进展和转移。因此,确定阻止这一过程的关键分子对于抑制肿瘤非常重要。白细胞介素-37(IL-37)可以通过IL-1R8或Smad3介导的途径抑制促炎细胞因子的产生。这里,我们证明,在Lewis肺癌(LLC)诱导的肺癌小鼠模型中,通过负向调节CCAAT/增强子结合蛋白β(C/EBPβ),人中性粒细胞IL-37被肿瘤细胞响应性降低,重组IL-37同工型d(IL-37d)显著抑制肺自发BMN迁移和肿瘤病变形成。机械上,IL-37d通过促进泛素连接酶COP1募集促进C/EBPβ泛素化降解并破坏C/EBPβDNA结合能力,从而减少中性粒细胞ATP的产生和迁移。我们的工作揭示了IL-37通过C/EBPβ的去稳定化来防止自发性BMN迁移和肿瘤进展的抗肿瘤机制。