LIGHT Signals Directly to Intestinal Epithelia to Cause Barrier Dysfunction via Cytoskeletal and Endocytic Mechanisms

Brad T. Schwarz, Fengjun Wang, Le Shen, Daniel R. Clayburgh, Liping Su, Yingmin Wang, Yang Xin Fu, Jerrold R. Turner

Research output: Contribution to journalArticle

129 Scopus citations

Abstract

Background & Aims: LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells) is a tumor necrosis factor core family member that regulates T-cell activation and causes experimental inflammatory bowel disease. Additional data suggest that LIGHT may be involved in the pathogenesis of human inflammatory bowel disease. The aim of this study was to determine if LIGHT is capable of signaling directly to intestinal epithelia and to define the mechanisms and consequences of such signaling. Methods: The effects of LIGHT and interferon-γ on barrier function, cytoskeletal regulation, and tight junction structure were assessed in mice and intestinal epithelial monolayers. Results: LIGHT induced barrier loss in cultured epithelia via myosin II regulatory light chain (MLC) phosphorylation; both barrier loss and MLC phosphorylation were reversed by MLC kinase (MLCK) inhibition. Pretreatment with interferon-γ, which induced lymphotoxin β receptor (LTβR) expression, was required for these effects, and neither barrier dysfunction nor intestinal epithelial MLC phosphorylation occurred in LTβR knockout mice. In cultured monolayers, endocytosis of the tight junction protein occludin correlated with barrier loss. Internalized occludin colocalized with caveolin-1. LIGHT-induced occludin endocytosis and barrier loss were both prevented by inhibition of caveolar endocytosis. Conclusions: T cell-derived LIGHT activates intestinal epithelial LTβR to disrupt barrier function. This requires MLCK activation and caveolar endocytosis. These data suggest a novel role for LIGHT in disease pathogenesis and suggest that inhibition of MLCK-dependent caveolar endocytosis may represent an approach to restoring barrier function in inflammatory bowel disease.

Original languageEnglish (US)
Pages (from-to)2383-2394
Number of pages12
JournalGastroenterology
Volume132
Issue number7
DOIs
StatePublished - Jun 2007

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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