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.
Keywords: C/EBPβ; CP: Cancer; CP: Immunology; IL-37d; neutrophils; spontaneous migration; tumor progression.
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