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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*,§

doi: 10.1097/01.MIB.0000437042.59208.9f
Original Basic Science Articles

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.

Article first published online 8 October 2013Supplemental Digital Content is Available in the Text.

*Department of Medicine, Division of Digestive Diseases, Emory University, Atlanta, Georgia;

Department of Physiology, University of Toronto, Ontario, Canada;

Department of Biology, Center for Diagnostics and Therapeutics, Suite 790 Petit Science Center, Georgia State University, Atlanta, Georgia;

§Veterans Affairs Medical Center, Decatur, Georgia;

Division of Gastroenterology, Beth Israel Deaconess Medical Centre, Harvard Medical School, Boston, Massachusetts; and

Department of Pathology and Laboratory Medicine, and

**Department of Physiology, Emory University, Atlanta, Georgia.

Reprints: Bindu Chandrasekharan, PhD, Department of Medicine, Division of Digestive Diseases, Emory University, Rm 265, Whitehead Research Bldg, 615 Michael St, Atlanta, GA 30322 (e-mail:

Supported by the Crohn's and Colitis Foundation of America: Career Development Award (BC), NIH-RO1 (DK080684, SS), VA-MERIT award (SS), DDRDC (DK064399, SS), DK06411 (SVS), DK59888 (AN), and DK080058 (EK).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

The authors have no conflicts of interest to disclose.

Received July 19, 2013

Accepted August 27, 2013

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