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Interactions between NF-κB and SP3 connect inflammatory signaling with reduced FGF-10 expression
Billy J Carver1, Erin J Plosa, Amanda M Stinnett
1Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
The Journal of Biological Chemistry
|April 6, 2013
Summary
Inflammation disrupts lung development by inhibiting FGF-10 gene expression. The study reveals that NF-κB and SP3 proteins interact to suppress FGF-10, impacting lung morphogenesis in preterm infants.
Area of Science:
- Developmental biology
- Molecular biology
- Immunology
Background:
- Inflammation impairs lung development in preterm infants.
- Soluble inflammatory mediators disrupt gene expression crucial for lung morphogenesis.
- Mechanisms linking innate immune signaling and developmental programs remain unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which inflammation inhibits lung development.
- To investigate the role of NF-κB signaling in regulating FGF-10 expression during lung morphogenesis.
- To identify the specific protein interactions involved in suppressing FGF-10.
Main Methods:
- Utilized chromatin immunoprecipitation (ChIP) in LPS-treated mouse fetal lung mesenchymal cells.
- Assessed Fgf-10 promoter activity using reporter assays.
- Manipulated NF-κB signaling pathway components (e.g., IKKβ, IκB) to study protein interactions and gene expression.
- Analyzed protein interactions using co-expression and dominant-negative constructs.
Main Results:
- NF-κB (RELA subunit) and SP3 interact to suppress SP1-mediated FGF-10 expression.
- SP3 co-expression antagonizes SP1 activity and reduces Fgf-10 promoter activity.
- Inflammatory stimuli (LPS) increase interactions between SP3, RELA, and the Fgf-10 promoter.
- NF-κB activation enhances RELA-SP3 nuclear interactions and inhibits FGF-10 expression.
Conclusions:
- Inflammatory signaling inhibits lung development by suppressing FGF-10 expression through NF-κB-dependent interactions between RELA and SP3 at the Fgf-10 promoter.
- NF-κB activation may reduce gene expression by recruiting inhibitory factors to target promoters.
- Understanding these pathways is critical for addressing bronchopulmonary dysplasia in preterm infants.
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