Abstract |
Total parenteral nutrition (TPN) is commonly used clinically to sustain patients; however, TPN is associated with profound mucosal atrophy, which may adversely affect clinical outcomes. Using a mouse TPN model, removing enteral nutrition leads to decreased crypt proliferation, increased intestinal epithelial cell (IEC) apoptosis and increased mucosal tumor necrosis factor alpha (TNF-α) expression that ultimately produces mucosal atrophy. Upregulation of TNF-α signaling plays a central role in mediating TPN-induced mucosal atrophy without intact epidermal growth factor receptor (EGFR) signaling. Currently, the mechanism and the tissue-specific contributions of TNF-α signaling to TPN-induced mucosal atrophy remain unclear. ADAM17 is an ectodomain sheddase that can modulate the signaling activity of several cytokine/ growth factor receptor families, including the TNF-α/ TNF receptor and ErbB ligand/EGFR pathways. Using TPN-treated IEC-specific ADAM17-deficient mice, the present study demonstrates that a loss of soluble TNF-α signaling from IECs attenuates TPN-induced mucosal atrophy. Importantly, this response remains dependent on the maintenance of functional EGFR signaling in IECs. TNF-α blockade in wild-type mice receiving TPN confirmed that soluble TNF-α signaling is responsible for downregulation of EGFR signaling in IECs. These results demonstrate that ADAM17-mediated TNF-α signaling from IECs has a significant role in the development of the proinflammatory state and mucosal atrophy observed in TPN-treated mice.
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Authors | Yongjia Feng, Yu-Hwai Tsai, Weidong Xiao, Matthew W Ralls, Alex Stoeck, Carole L Wilson, Elaine W Raines, Daniel H Teitelbaum, Peter J Dempsey |
Journal | Molecular and cellular biology
(Mol Cell Biol)
Vol. 35
Issue 21
Pg. 3604-21
(Nov 2015)
ISSN: 1098-5549 [Electronic] United States |
PMID | 26283731
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2015, American Society for Microbiology. All Rights Reserved. |
Chemical References |
- Cytokines
- STAT3 Transcription Factor
- Tumor Necrosis Factor-alpha
- ErbB Receptors
- ADAM Proteins
- ADAM17 Protein
- ADAM17 protein, human
- Adam17 protein, mouse
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Topics |
- ADAM Proteins
(genetics, immunology)
- ADAM17 Protein
- Animals
- Apoptosis
- Atrophy
(immunology, pathology)
- Cell Proliferation
- Cytokines
(immunology)
- ErbB Receptors
(immunology)
- Female
- Gene Knockout Techniques
- Humans
- Intestinal Mucosa
(cytology, immunology, metabolism, pathology)
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Parenteral Nutrition, Total
(adverse effects)
- STAT3 Transcription Factor
(immunology)
- Signal Transduction
- Tumor Necrosis Factor-alpha
(immunology)
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