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Author Notes:

Corresponding Author: Bindu Chandrasekharan, Ph.D., Associate in Medicine (Research Track), Division of Digestive Diseases, Department of Medicine, Emory University, Rm 265, Whitehead Research Bldg, 615 Michael St, Atlanta, GA-30322, bchandr@emory.edu, Tel: 404-727-6234, Fax: 404-727-5767

Competing Interests: None


Research Funding:

This work is funded by the Crohn’s and Colitis Foundation of America Career Development Award (BC), NIH-RO1 (DK080684, SS), VA-MERIT award (SS) and DDRDC (DK064399, SS), DK06411 (SVS), DK59888 (AN) and DK080058 (EK)


  • Science & Technology
  • Life Sciences & Biomedicine
  • Gastroenterology & Hepatology
  • NPY
  • TNF
  • enteric neurons
  • experimental colitis
  • barrier functions
  • colonic motility

Tumor Necrosis Factor-Neuropeptide Y Cross Talk Regulates Inflammation, Epithelial Barrier Functions, and Colonic Motility


Journal Title:

Inflammatory Bowel Diseases


Volume 19, Number 12


, Pages 2535-2546

Type of Work:

Article | Post-print: After Peer Review


Background: Neuro-immune interactions play a significant role in regulating the severity of inflammation. Our previous work demonstrated that neuropeptide Y (NPY) is upregulated in the enteric nervous system during murine colitis and that NPY knockout mice exhibit reduced inflammation. Here, we investigated if NPY expression during inflammation is induced by tumor necrosis factor (TNF), the main proinflammatory cytokine. Methods: Using primary enteric neurons and colon explant cultures from wild type and NPY knockout (NPY-/-) mice, we determined if NPY knockdown modulates TNF release and epithelial permeability. Further, we assessed if NPY expression is inducible by TNF in enteric neuronal cells and mouse model of experimental colitis, using the TNF inhibitors-etanercept (blocks transmembrane and soluble TNF) and XPro1595 (blocks soluble TNF only). Results: We found that enteric neurons express TNF receptors (TNFR1 and R2). Primary enteric neurons from NPY-/- mice produced less TNF compared with wild type. Further, TNF activated NPY promoter in enteric neurons through phospho-c-Jun. NPY-/- mice had decreased intestinal permeability. In vitro, NPY increased epithelial permeability through phosphatidyl inositol-3-kinase (PI3-K)-induced pore-forming claudin-2. TNF inhibitors attenuated NPY expression in vitro and in vivo. TNF inhibitor-treated colitic mice exhibited reduced NPY expression and inflammation, reduced oxidative stress, enhanced neuronal survival, and improved colonic motility. XPro1595 had more protective effects on neuronal survival and motility compared with etanercept. Conclusions: We demonstrate a novel TNF-NPY cross talk that modulates inflammation, barrier functions, and colonic motility during inflammation. It is also suggested that selective blocking of soluble TNF may be a better therapeutic option than using anti-TNF antibodies.

Copyright information:

© 2013 Crohn's & Colitis Foundation of America, Inc.

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