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Smad7 interrupts TGF-β signaling in intestinal macrophages and promotes inflammatory activation of these cells during necrotizing enterocolitis
- Source :
- Pediatric research
- Publication Year :
- 2016
- Publisher :
- Springer Science and Business Media LLC, 2016.
-
Abstract
- Background Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants. Based on our recent findings of increased Smad7 expression in surgically-resected bowel affected by NEC, we hypothesized that NEC macrophages undergo inflammatory activation because increased Smad7 expression renders these cells resistant to normal, gut-specific, transforming growth factor (TGF)-β-mediated suppression of inflammatory pathways. Methods We used surgically-resected human NEC tissue, murine models of NEC-like injury, bone marrow-derived and intestinal macrophages, and RAW264.7 cells. Smad7 and IκB kinase-beta (IKK-β) were measured by quantitative polymerase chain reaction (qPCR), Western blots, and immunohistochemistry. Promoter activation was confirmed in luciferase reporter and chromatin immunoprecipitation assays. Results NEC macrophages showed increased Smad7 expression, particularly in areas with severe tissue damage and high bacterial load. LPS-induced Smad7 expression suppressed TGF-β signaling and augmented NF-κB activation and cytokine production in macrophages. Smad7-mediated NF-κB activated was likely mediated via increased expression of IKK-β, which, further increased Smad7 expression in a feed-forward loop. We show that Smad7 induced IKK-β expression through direct binding to the IKK-β promoter and its transcriptional activation. Conclusions Smad7 expression in NEC macrophages interrupts TGF-β signaling and promotes NF-κB-mediated inflammatory signaling in these cells through increased expression of IKK-β.
- Subjects :
- Lipopolysaccharides
0301 basic medicine
medicine.medical_treatment
Inflammation
IκB kinase
Article
Smad7 Protein
Mice
03 medical and health sciences
0302 clinical medicine
Enterocolitis, Necrotizing
Transforming Growth Factor beta
medicine
Animals
Humans
Intestinal Mucosa
integumentary system
biology
business.industry
Macrophages
NF-kappa B
Transforming growth factor beta
medicine.disease
NFKB1
digestive system diseases
I-kappa B Kinase
Mice, Inbred C57BL
RAW 264.7 Cells
030104 developmental biology
Cytokine
Pediatrics, Perinatology and Child Health
Necrotizing enterocolitis
Immunology
Cancer research
biology.protein
medicine.symptom
Signal transduction
business
030217 neurology & neurosurgery
Signal Transduction
Transforming growth factor
Subjects
Details
- ISSN :
- 15300447 and 00313998
- Volume :
- 79
- Database :
- OpenAIRE
- Journal :
- Pediatric Research
- Accession number :
- edsair.doi.dedup.....f376b0ad92888e232fdd0415586aba3b