Skip Navigation LinksHome > November 2013 - Volume 19 - Issue 12 > Tumor Necrosis Factor–Neuropeptide Y Cross Talk Regulates In...
Inflammatory Bowel Diseases:
doi: 10.1097/01.MIB.0000437042.59208.9f
Original Basic Science Articles

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

Chandrasekharan, Bindu PhD*; Jeppsson, Sabrina BA*; Pienkowski, Stefan BA*; Belsham, Denise D. PhD; Sitaraman, Shanthi V. MD, PhD*; Merlin, Didier PhD‡,§; Kokkotou, Efi MD, PhD, DSc; Nusrat, Asma MD; Tansey, Malu G. PhD**; Srinivasan, Shanthi MD*,§

Supplemental Author Material
Collapse Box

Abstract

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

You currently do not have access to this article.

You may need to:

Note: If your society membership provides for full-access to this article, you may need to login on your society’s web site first.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.