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Loss of ADAM17-Mediated Tumor Necrosis Factor Alpha Signaling in Intestinal Cells Attenuates Mucosal Atrophy in a Mouse Model of Parenteral Nutrition.

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.
AuthorsYongjia Feng, Yu-Hwai Tsai, Weidong Xiao, Matthew W Ralls, Alex Stoeck, Carole L Wilson, Elaine W Raines, Daniel H Teitelbaum, Peter J Dempsey
JournalMolecular and cellular biology (Mol Cell Biol) Vol. 35 Issue 21 Pg. 3604-21 (Nov 2015) ISSN: 1098-5549 [Electronic] United States
PMID26283731 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 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
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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