Error message

No crossref credentials set for jbc

AMP-activated Protein Kinase Mediates the Interferon-γ-induced Decrease in Intestinal Epithelial Barrier Function

J. Biol. Chem., 9 October 2009
Vol. 284, Issue 41, p. 27952-27963
DOI: 10.1074/jbc.M109.046292

AMP-activated Protein Kinase Mediates the Interferon-γ-induced Decrease in Intestinal Epithelial Barrier Function

  1. Michael Scharl,
  2. Gisela Paul,
  3. Kim E. Barrett and
  4. Declan F. McCole1
  1. From the Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, California 92093
  1. 1 To whom correspondence should be addressed: Division of Gastroenterology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0063. Tel.: 858-534-2794; Fax: 858-534-3338; E-mail: dmccole{at}


Impaired epithelial barrier function plays a crucial role in the pathogenesis of inflammatory bowel disease. Elevated levels of the pro-inflammatory cytokine, interferon-γ (IFNγ), are believed to be prominently involved in the pathogenesis of Crohn disease. Treatment of T84 intestinal epithelial cells with IFNγ severely impairs their barrier properties measured as transepithelial electrical resistance (TER) or permeability and reduces the expression of tight junction proteins such as occludin and zonula occludens-1 (ZO-1). However, little is known about the signaling events that are involved. The cellular energy sensor, AMP-activated protein kinase (AMPK), is activated in response to cellular stress, as occurs during inflammation. The aim of this study was to investigate a possible role for AMPK in mediating IFNγ-induced effects on the intestinal epithelial barrier. We found that IFNγ activates AMPK by phosphorylation, independent of intracellular energy levels. Inhibition of AMPK prevents, at least in part, the IFNγ-induced decrease in TER. Furthermore, AMPK knockdown prevented the increased epithelial permeability, the decreased TER, and the decrease in occludin and ZO-1 caused by IFNγ treatment of T84 cells. However, AMPK activity alone was not sufficient to cause alterations in epithelial barrier function. These data show a novel role for AMPK, in concert with other signals induced by IFNγ, in mediating reduced epithelial barrier function in a cell model of chronic intestinal inflammation. These findings may implicate AMPK in the pathogenesis of chronic intestinal inflammatory conditions, such as inflammatory bowel disease.


  • * This work was supported, in whole or in part, by National Institutes of Health Grant DK080506. This work was also supported by a Career Development Award and a Senior Research Award from the Crohn's and Colitis Foundation of America (to D. F. M.), scholarships from the German Research Foundation (Deutsche Forschungsgemeinschaft) (to M. S. and G. P.), and by the UCSD Digestive Diseases Research Development Center.

  • Received July 20, 2009.
  • Revision received August 3, 2009.


M. Scharl, G. Paul, K. E. Barrett, and D. F. McCole, AMP-activated Protein Kinase Mediates the Interferon-γ-induced Decrease in Intestinal Epithelial Barrier Function. J. Biol. Chem. 284, 27952-27963 (2009).

Spermidine Stimulates T Cell Protein-tyrosine Phosphatase-mediated Protection of Intestinal Epithelial Barrier Function
H. M. Penrose, R. R. Marchelletta, M. Krishnan, and D. F. McCole
J Biol Chem 288, 32651-32662 (8 November 2013)

Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF-{alpha} on tight junction proteins and signaling pathways in intestinal epithelial cells
A. Fischer, M. Gluth, U.-F. Pape, B. Wiedenmann, F. Theuring, and D. C. Baumgart
Am. J. Physiol. Gastrointest. Liver Physiol. 304, G970-G979 (1 June 2013)

Interferon-{gamma} Activates Transglutaminase 2 via a Phosphatidylinositol-3-Kinase-Dependent Pathway: Implications for Celiac Sprue Therapy
T. R. DiRaimondo, C. Klock, and C. Khosla
J. Pharmacol. Exp. Ther. 341, 104-114 (1 April 2012)

Interferon-{gamma} Alters Downstream Signaling Originating from Epidermal Growth Factor Receptor in Intestinal Epithelial Cells: FUNCTIONAL CONSEQUENCES FOR ION TRANSPORT
G. Paul, R. R. Marchelletta, D. F. McCole, and K. E. Barrett
J Biol Chem 287, 2144-2155 (13 January 2012)

Transforming Growth Factor-{beta}, a Whey Protein Component, Strengthens the Intestinal Barrier by Upregulating Claudin-4 in HT-29/B6 Cells
N. A. Hering, S. Andres, A. Fromm, E. A. van Tol, M. Amasheh, J. Mankertz, M. Fromm, and J. D. Schulzke
J. Nutr. 141, 783-789 (1 May 2011)

Epithelial Myosin Light Chain Kinase Activation Induces Mucosal Interleukin-13 Expression to Alter Tight Junction Ion Selectivity
C. R. Weber, D. R. Raleigh, L. Su, L. Shen, E. A. Sullivan, Y. Wang, and J. R. Turner
J Biol Chem 285, 12037-12046 (16 April 2010)

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882