JOURNAL ARTICLE

Lingual antimicrobial peptide and IL-8 expression are oppositely regulated by the antagonistic effects of NF-κB p65 and C/EBPβ in mammary epithelial cells

Shuzhen Liu, Xuanming Shi, Isabel Bauer, Juliane Günther, Hans-Martin Seyfert
Molecular Immunology 2011, 48 (6-7): 895-908
21255844
Pathogen contact induces quickly in Mammary Epithelial Cells (MEC) the expression of the proinflammatory cytokine IL-8 and delayed that of the bactericidal β-defensin LAP. Both genes encoding these factors feature on their proximal promoter a composite NF-κB/CEBP binding site. We compare here in MEC the role of NF-κB and C/EBP factors in regulating basal and pathogen-induced expression of both genes from cattle. Abrogating NF-κB binding to that site by introduction of a single point mutation blocks promoter activity of both genes in reporter gene assays. Chromatin accessibility PCR and Chromatin immunoprecipitation reveal that the chromatin of the resting LAP promoter is tightly packed and NF-κB p50 homodimer binding prevails. Infection results in chromatin decompaction accompanied by predominant recruitment of NF-κB p65 for promoter activation. Overexpression of transcription factors confirms a stimulatory role of NF-κB p65 but also a repressive function of C/EBPβ for LAP promoter activity. These factors reverse roles to control IL-8 expression. NF-κB p65 homodimers already reside on the resting IL-8 promoter and induction recruits NF-κB p50. Overexpression of both NF-κB factors represses the promoter in MEC, but not in HEK293 cells. Inhibitors of NF-κB activation and nuclear recruitment both tremendously increase basal and pathogen stimulated IL-8 mRNA concentrations in MEC. Mutation of the C/EBP-binding site blocks and overexpression of C/EBPβ stimulates IL-8-promoter activity. Thus, the pathogen-induced fast activation of diverse transcription factors acting through a common promoter binding site is gene specifically differentiated into opposite functional significance for swiftly (IL-8) or slowly (LAP) induced genes in MEC.

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