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

Abstract

BACKGROUND & AIMS-LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpes virus entry on T cells) is a TNF 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 was capable of signaling directly to intestinal epithelia and to define the mechanisms and consequences of such signaling.

PGE2promotes Ca2+-mediated epithelial barrier disruption through EP1and EP4receptors in Caco-2 cell monolayers

“…In this respect, the presence of cytosolic occludin is associated with protein internalization by endocytosis. In the case of barrier loss induced by TNF-␣, occludin internalization was described as a MLCK-dependent process (38). The results obtained here in Caco-2 cells indicate that the increase in PP may correlate with the redistribution of TJ .…”

Inhibition of long myosin light-chain kinase activation alleviates intestinal damage after binge ethanol exposure and burn injury

“…Of these cytokines, most studies have focused on TNF-␣ in barrier dysfunction. TNF-␣ was shown to directly upregulate MLCK transcription as well as protein levels (25,54) and the cytokine also promotes occludin internalization (12,45). In models of inflammatory bowel disease, antagonism of TNF-␣ resulted in partial restoration of T-cell mediated barrier dysfunction (11); however, in our model of binge ethanol exposure and burn injury, we only see an early rise in serum levels of TNF-␣.…”

Occludin is required for cytokine-induced regulation of tight junction barriers

“…More recently, it has been recognized that occludin endocytosis is a common feature of responses not only to cytokine treatment but also to exposure to bacteria, toxins (Yu and Turner, 2008) or some viruses (Coyne et al, 2007;Liu et al, 2009). This endocytosis coincides with and is required for barrier disruption, since blocking endocytosis prevents cytokine-or toxin-induced increases in tight junction permeability (Shen and Turner, 2005;Clayburgh et al, 2005;Schwarz et al, 2007). In addition, there is recent in vivo evidence for cytokine-induced occludin endocytosis, using genetically modified mice expressing GFP-occludin (Marchiando et al, 2010).…”