FBXW7alpha attenuates inflammatory signaling by suppressing expression of Cebpd and its target gene Tlr4

Thursday, October 11, 2012 — Poster Session IV
2:00 p.m. – 4:00 p.m.	Natcher Conference Center, Building 45	NCI	IMMUNO-4

Authors

• K Balamurugan
• KD Klarmann
• Y Zhang
• V Coppola
• GH Summers
• T Roger
• JR Keller
• S Sharan
• E Sterneck

Abstract

The lipopolysaccharide (LPS) receptor Toll-like receptor 4 (TLR4) plays a pivotal role in mediating innate immune responses for the host defense against pathogens. TLR4 signaling activates NF-kB transcription factors that induce inflammatory response genes such as CCAAT/enhancer binding protein delta (C/EBPd, CEBPD). Here we show that C/EBPd is also necessary for TLR4 gene expression and therefore central to the endotoxin response. Previously we reported that C/EBPd promotes HIF-1a expression and hypoxia adaptation in mammary tumor cells through inhibition of the tumor suppressor F-box and WD repeat domain containing protein 7 (FBXW7, FBW7, CDC4), which was correlated with metastatic progression. Here we show that inhibition of FBXW7 promotes hypoxia and inflammatory responses in macrophages. Ectopic FBXW7 reduced C/EBPd expression and abolished LPS responses whereas FBXW7 depletion augmented C/EBPd/TLR4-mediated signaling. Inflammation is also well associated with cancer progression. In C/EBPd null mice, mammary tumors showed diminished TLR4 expression and reduced pro-inflammatory markers in vivo, which is in agreement with their reduced metastatic potential. Taken together, these findings reveal an essential role for C/EBPd in TLR4 signaling and uncover a novel function for FBXW7 as an attenuator of innate immune responses.

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