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FBXW7? attenuates inflammatory signalling by downregulating C/EBP? and its target gene Tlr4.

ABSTRACT: Toll-like receptor 4 (Tlr4) has a pivotal role in innate immune responses, and the transcription factor CCAAT/enhancer binding protein delta (C/EBP?, Cebpd) is a Tlr4-induced gene. Here we identify a positive feedback loop in which C/EBP? activates Tlr4 gene expression in macrophages and tumour cells. In addition, we discovered a negative feedback loop whereby the tumour suppressor FBXW7? (FBW7, Cdc4), whose gene expression is inhibited by C/EBP?, targets C/EBP? for degradation when C/EBP? is phosphorylated by GSK-3?. Consequently, FBXW7? suppresses Tlr4 expression and responses to the ligand lipopolysaccharide. FBXW7? 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/EBP? upstream of Tlr4 signalling and uncover a function for FBXW7? as an attenuator of inflammatory signalling.

SUBMITTER: Balamurugan K

PROVIDER: S-EPMC3625980 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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

Balamurugan Kuppusamy K Sharan Shikha S Klarmann Kimberly D KD Zhang Youhong Y Coppola Vincenzo V Summers Glenn H GH Roger Thierry T Morrison Deborah K DK Keller Jonathan R JR Sterneck Esta E

Nature communications 20130101

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 ph ...[more]

PMID: 23575666

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Project description:ObjectiveEosinophils reside in the colonic mucosa and increase significantly during disease. Although a number of studies have suggested that eosinophils contribute to the pathogenesis of GI inflammation, the expanding scope of eosinophil-mediated activities indicate that they also regulate local immune responses and modulate tissue inflammation. We sought to define the impact of eosinophils that respond to acute phases of colitis in mice.DesignAcute colitis was induced in mice by administration of dextran sulfate sodium, 2,4,6-trinitrobenzenesulfonic acid or oxazolone to C57BL/6J (control) or eosinophil deficient (PHIL) mice. Eosinophils were also depleted from mice using antibodies against interleukin (IL)-5 or by grafting bone marrow from PHIL mice into control mice. Colon tissues were collected and analysed by immunohistochemistry, flow cytometry and reverse transcription PCR; lipids were analysed by mass spectroscopy.ResultsEosinophil-deficient mice developed significantly more severe colitis, and their colon tissues contained a greater number of neutrophils, than controls. This compensatory increase in neutrophils was accompanied by increased levels of the chemokines CXCL1 and CXCL2, which attract neutrophils. Lipidomic analyses of colonic tissue from eosinophil-deficient mice identified a deficiency in the docosahexaenoic acid-derived anti-inflammatory mediator 10, 17- dihydroxydocosahexaenoic acid (diHDoHE), namely protectin D1 (PD1). Administration of an exogenous PD1-isomer (10S, 17S-DiHDoHE) reduced the severity of colitis in eosinophil-deficient mice. The PD1-isomer also attenuated neutrophil infiltration and reduced levels of tumour necrosis factor-α, IL-1β, IL-6 and inducible NO-synthase in colons of mice. Finally, in vitro assays identified a direct inhibitory effect of PD1-isomer on neutrophil transepithelial migration.ConclusionsEosinophils exert a protective effect in acute mouse colitis, via production of anti-inflammatory lipid mediators.

Dataset Information

FBXW7? attenuates inflammatory signalling by downregulating C/EBP? and its target gene Tlr4.

Publications

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

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