Abstract
The intestinal epithelial tight junction (TJ) barrier controls the paracellular permeation of contents from the intestinal lumen into the intestinal tissue and systemic circulation. A defective intestinal TJ barrier has been implicated as an important pathogenic factor in inflammatory diseases of the gut including Crohn’s disease, ulcerative colitis, necrotizing enterocolitis, and celiac disease. Previous studies have shown that pro-inflammatory cytokines, which are produced during intestinal inflammation, including interleukin-1β (IL-1β), tumor necrosis factor-α, and interferon-γ, have important intestinal TJ barrier-modulating actions. Recent studies have shown that the IL-1β-induced increase in intestinal TJ permeability is an important contributing factor of intestinal inflammation. The IL-1β-induced increase in intestinal TJ permeability is mediated by regulatory signaling pathways and activation of nuclear transcription factor nuclear factor-κB, myosin light chain kinase gene activation, and post-transcriptional occludin gene modulation by microRNA and contributes to the intestinal inflammatory process. In this review, the regulatory role of IL-1β on intestinal TJ barrier, the intracellular mechanisms that mediate the IL-1β modulation of intestinal TJ permeability, and the potential therapeutic targeting of the TJ barrier are discussed.
Highlights
The gastrointestinal (GI) tract is lined by a single cell layer of intestinal epithelial cells (IECs) which serve as a physical barrier against the influx of luminally located noxious substances, large hydrophilic molecules, and bacterial organisms [1, 2]
IL-1b is a pluripotent pro-inflammatory cytokine that is elevated in various inflammatory diseases, including necrotizing enterocolitis (NEC), irritable bowel syndrome, infectious diarrhea, and inflammatory bowel disease (IBD)
A key hallmark of IBD is intestinal epithelial tight junction (TJ) barrier disruption manifested by an increase in intestinal permeability [71, 140, 159]; the precise factors which contribute to the defective intestinal TJ barrier and the role IL-1b plays in the barrier defect remains unclear
Summary
The gastrointestinal (GI) tract is lined by a single cell layer of intestinal epithelial cells (IECs) which serve as a physical barrier against the influx of luminally located noxious substances, large hydrophilic molecules, and bacterial organisms [1, 2]. Previous studies have shown that the p38 kinase signaling cascade contributes to IL-1b-induced increased MLCK expression and increased intestinal TJ permeability in vitro and in vivo [46] These studies found that IL-1b induced a rapid phosphorylation and activation of p38 kinase and downstream activation of a p38-dependent transcription factor, activating transcription factor-2 (ATF-2); the activated ATF-2 translocated to the nucleus and attached to the binding motif on the MLCK promoter region, leading to MLCK gene activation and protein synthesis, and MLCK-dependent opening of the intestinal TJ barrier [46]. The effect of IL-1b-induced increase in Caco-2 TJ permeability was proposed to be mediated by an increase in p38 kinase phosphorylation, leading to an increase in MLCK gene and protein expression and FIGURE 3 | Schematic diagram of the potential role of the interleukin-1b (IL-1b)-induced increase in microRNA-200c-3p expression and intestinal tight junction (TJ) permeability in modulating intestinal inflammation. The results of studies evaluating the effect of IL-1b on claudin proteins have been inconsistent; some studies suggested that IL-1b has no effect, while others have suggested that IL-1b downregulates claudin-3 or causes an alteration in ZO-1, claudin-1, and claudin-7 junctional localization in a MLCK-dependent manner
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