Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA.
Nat Commun. 2013;4:1662. doi: 10.1038/ncomms2677.
Toll-like receptor 4 (Tlr4) has a pivotal role in innate immune responses, and the transcription factor CCAAT/enhancer binding protein delta (C/EBPδ, Cebpd) is a Tlr4-induced gene. Here we identify a positive feedback loop in which C/EBPδ activates Tlr4 gene expression in macrophages and tumour cells. In addition, we discovered a negative feedback loop whereby the tumour suppressor FBXW7α (FBW7, Cdc4), whose gene expression is inhibited by C/EBPδ, targets C/EBPδ for degradation when C/EBPδ is phosphorylated by GSK-3β. Consequently, FBXW7α suppresses Tlr4 expression and responses to the ligand lipopolysaccharide. FBXW7α depletion alone is sufficient to augment pro-inflammatory signalling in vivo. Moreover, as inflammatory pathways are known to modulate tumour biology, Cebpd null mammary tumours, which have reduced metastatic potential, show altered expression of inflammation-associated genes. Together, these findings reveal a role for C/EBPδ upstream of Tlr4 signalling and uncover a function for FBXW7α as an attenuator of inflammatory signalling.
Toll 样受体 4（Tlr4）在先天免疫反应中起着关键作用，转录因子 CCAAT/增强子结合蛋白 δ（C/EBPδ，Cebpd）是 Tlr4 诱导的基因。在这里，我们确定了一个正反馈回路，其中 C/EBPδ 在巨噬细胞和肿瘤细胞中激活 Tlr4 基因表达。此外，我们发现了一个负反馈回路，其中肿瘤抑制因子 FBXW7α（FBW7，Cdc4）的基因表达被 C/EBPδ 抑制，当 C/EBPδ 被 GSK-3β 磷酸化时，FBXW7α 将 C/EBPδ 靶向降解。因此，FBXW7α 抑制 Tlr4 表达和对配体脂多糖的反应。FBXW7α 的单独耗竭足以在体内增强促炎信号。此外，由于已知炎症途径可调节肿瘤生物学，因此具有降低转移潜力的 Cebpd 缺失乳腺肿瘤显示出与炎症相关基因的表达改变。总之，这些发现揭示了 C/EBPδ 在 Tlr4 信号上游的作用，并揭示了 FBXW7α 作为炎症信号减弱剂的功能。
