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LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms.
Gastroenterology. 2007 Jun; 132(7):2383-94.G

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-gamma 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-gamma, which induced lymphotoxin beta receptor (LT beta R) expression, was required for these effects, and neither barrier dysfunction nor intestinal epithelial MLC phosphorylation occurred in LT beta R 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 LT beta R 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.

Authors+Show Affiliations

Department of Pathology, University of Chicago, Chicago, Illinois 60637, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17570213

Citation

Schwarz, Brad T., et al. "LIGHT Signals Directly to Intestinal Epithelia to Cause Barrier Dysfunction Via Cytoskeletal and Endocytic Mechanisms." Gastroenterology, vol. 132, no. 7, 2007, pp. 2383-94.
Schwarz BT, Wang F, Shen L, et al. LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms. Gastroenterology. 2007;132(7):2383-94.
Schwarz, B. T., Wang, F., Shen, L., Clayburgh, D. R., Su, L., Wang, Y., Fu, Y. X., & Turner, J. R. (2007). LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms. Gastroenterology, 132(7), 2383-94.
Schwarz BT, et al. LIGHT Signals Directly to Intestinal Epithelia to Cause Barrier Dysfunction Via Cytoskeletal and Endocytic Mechanisms. Gastroenterology. 2007;132(7):2383-94. PubMed PMID: 17570213.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms. AU - Schwarz,Brad T, AU - Wang,Fengjun, AU - Shen,Le, AU - Clayburgh,Daniel R, AU - Su,Liping, AU - Wang,Yingmin, AU - Fu,Yang-Xin, AU - Turner,Jerrold R, Y1 - 2007/02/27/ PY - 2007/01/15/received PY - 2007/02/15/accepted PY - 2007/6/16/pubmed PY - 2007/7/25/medline PY - 2007/6/16/entrez SP - 2383 EP - 94 JF - Gastroenterology JO - Gastroenterology VL - 132 IS - 7 N2 - 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-gamma 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-gamma, which induced lymphotoxin beta receptor (LT beta R) expression, was required for these effects, and neither barrier dysfunction nor intestinal epithelial MLC phosphorylation occurred in LT beta R 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 LT beta R 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. SN - 0016-5085 UR - https://www.unboundmedicine.com/medline/citation/17570213/LIGHT_signals_directly_to_intestinal_epithelia_to_cause_barrier_dysfunction_via_cytoskeletal_and_endocytic_mechanisms_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0016-5085(07)00411-8 DB - PRIME DP - Unbound Medicine ER -