IFN-γ-Induced TNFR2 Expression Is Required for TNF-Dependent Intestinal Epithelial Barrier Dysfunction

Fengjun Wang, Brad T. Schwarz, W. Vallen Graham, Yingmin Wang, Liping Su, Daniel R. Clayburgh, Clara Abraham, Jerrold R. Turner

Research output: Contribution to journalArticle

199 Scopus citations

Abstract

Background & Aims: 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. Methods: 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. Results: Colitis induced in vivo by adoptive transfer of CD4+CD45RBhi 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)-γ pretreatment. This reductionist model was therefore used to determine the molecular mechanism by which IFN-γ and TNF synergize to cause intestinal epithelial barrier loss. IFN-γ 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-γ-independent TNF responses. Conclusions: IFN-γ 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.

Original languageEnglish (US)
Pages (from-to)1153-1163
Number of pages11
JournalGastroenterology
Volume131
Issue number4
DOIs
StatePublished - Oct 2006

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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