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Nat Commun. 2013;4:1662. doi: 10.1038/ncomms2677.

FBXW7α attenuates inflammatory signalling by downregulating C/EBPδ and its target gene Tlr4.

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  • 1Laboratory of Cell and Developmental Signalling, National Cancer Institute-Frederick, PO Box B, Frederick, Maryland 21702-1201, USA.

Abstract

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.

PMID:
23575666
PMCID:
PMC3625980
DOI:
10.1038/ncomms2677
[PubMed - indexed for MEDLINE]
Free PMC Article
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