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PMID: 17030185 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction.

Gastroenterology ·Vol. 131 ·No. 4 ·2006-10-00 ·Pages 1153-63

Wang F, Schwarz BT, Graham WV, Wang Y, Su L, Clayburgh DR, Abraham C, Turner JR

Abstract

Tumor necrosis factor (TNF) plays a critical role in intestinal disease. In intestinal epithelia, TNF causes tight junction disruption and epithelial barrier loss by up-regulating myosin light chain kinase (MLCK) activity and expression. The aim of this study was to determine the signaling pathways by which TNF causes intestinal epithelial barrier loss. Caco-2 cells that were either nontransfected or stably transfected with human TNF receptor 1 (TNFR1) or TNFR2 and mouse colonocytes were used for physiologic, morphologic, and biochemical analyses. Colitis induced in vivo by adoptive transfer of CD4(+)CD45RB(hi) T cells was associated with increased epithelial MLCK expression and myosin II regulatory light chain (MLC) phosphorylation as well as morphologic tight junction disruption. In vitro studies showed that TNF caused similar increases in MLCK expression and MLC phosphorylation, as well as barrier dysfunction, in Caco-2 monolayers only after interferon (IFN)-gamma pretreatment. This reductionist model was therefore used to determine the molecular mechanism by which IFN-gamma and TNF synergize to cause intestinal epithelial barrier loss. IFN-gamma priming increased TNFR1 and TNFR2 expression, and blocking antibody studies showed that TNFR2, but not TNFR1, was required for TNF-induced barrier dysfunction. Transgenic TNFR2, but not TNFR1, expression allowed IFN-gamma-independent TNF responses. IFN-gamma primes intestinal epithelia to respond to TNF by inducing TNFR2 expression, which in turn mediates TNF-induced MLCK-dependent barrier dysfunction. The data further suggest that epithelial TNFR2 blockade may be a novel approach to restore barrier function in intestinal disease.

MeSH Terms
Animals Caco-2 Cells Homeodomain Proteins/genetics Humans Interferon-gamma/metabolism,pharmacology Intestinal Diseases/metabolism,pathology,physiopathology Intestinal Mucosa/drug effects,metabolism,pathology Mice Mice, Inbred C57BL Mice, Mutant Strains Myosin Light Chains/metabolism Myosin-Light-Chain Kinase/genetics,metabolism Phosphorylation Receptors, Tumor Necrosis Factor/genetics,metabolism Signal Transduction/drug effects,physiology Tight Junctions/drug effects,metabolism,pathology Tumor Necrosis Factor-alpha/metabolism Up-Regulation/physiology
Chemicals
Homeodomain Proteins Myosin Light Chains Receptors, Tumor Necrosis Factor Tnfrh2 protein, mouse Tnfrsf23 protein, mouse Tumor Necrosis Factor-alpha RAG-1 protein Interferon-gamma Myosin-Light-Chain Kinase
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Wang Fengjun
State Key Laboratory of Trauma, Burns, and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing, China.
Schwarz Brad T
Graham W Vallen
Wang Yingmin
Su Liping
Clayburgh Daniel R
Abraham Clara
Turner Jerrold R
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Article Info
Journal
Gastroenterology
Abbr.
Gastroenterology
ISSN
0016-5085
DOI
10.1053/j.gastro.2006.08.022
Published
2006-10-00
Epub
2006-00-22
Pages
1153-63
Language
English
Region
United States
NLM ID
0374630
PMCID
PMC1693969
Subset
IM
Grants
NIDDK NIH HHS · P30 DK042086 · United States
NIDDK NIH HHS · DK 42086 · United States
NCI NIH HHS · CA 14599 · United States
NIDDK NIH HHS · DK 68271 · United States
NCI NIH HHS · P30 CA014599 · United States
NIDDK NIH HHS · R01 DK061931 · United States
NIDDK NIH HHS · R01 DK068271 · United States
NIDDK NIH HHS · DK 61931 · United States
External Links
PubMed source DOI: 10.1053/j.gastro.2006.08.022 PMC Full Text View journal details
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