Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo.

Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. Research Abstract Details 

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Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. Abstract Text:

Acute T cell-mediated diarrhea is associated with increased mucosal expression of proinflammatory cytokines, including the TNF superfamily members TNF and LIGHT. While we have previously shown that epithelial barrier dysfunction induced by myosin light chain kinase (MLCK) is required for the development of diarrhea, MLCK inhibition does not completely restore water absorption. In contrast, although TNF-neutralizing antibodies completely restore water absorption after systemic T cell activation, barrier function is only partially corrected. This suggests that, while barrier dysfunction is critical, other processes must be involved in T cell-mediated diarrhea. To define these processes in vivo, we asked whether individual cytokines might regulate different events in T cell-mediated diarrhea. Both TNF and LIGHT caused MLCK-dependent barrier dysfunction. However, while TNF caused diarrhea, LIGHT enhanced intestinal water absorption. Moreover, TNF, but not LIGHT, inhibited Na+ absorption due to TNF-induced internalization of the brush border Na+/H+ exchanger NHE3. LIGHT did not cause NHE3 internalization. PKCalpha activation by TNF was responsible for NHE3 internalization, and pharmacological or genetic PKCalpha inhibition prevented NHE3 internalization, Na+ malabsorption, and diarrhea despite continued barrier dysfunction. These data demonstrate the necessity of coordinated Na+ malabsorption and barrier dysfunction in TNF-induced diarrhea and provide insight into mechanisms of intestinal water transport.

Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. Publishing Authors By Initials

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Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: The Journal of clinical investigation

VOLUME: 116

Page Numbers: 2682-94

Journal Abbreviation: J. Clin. Invest.

ISSN: 0021-9738

DAY: 3

MONTH: Oct

YEAR: 2006

Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7802877

Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. Keywords Mesh Terms:

KEYWORDS: Water

MESH TERMS: metabolism

Chemical & Substance for Abstract: Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. Information

Substance Name: Protein Kinase C-alpha

Registry Number: EC 2.7.1.37

Grant and Affiliation Information for Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo.

AFFILIATION: Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: T32 GM07281

ACRONYM: GM

MEDLINETA: J Clin Invest

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