Helicobacter pylori Activates Myosin Light-Chain Kinase To Disrupt Claudin-4 and Claudin-5 and Increase Epithelial Permeability

Abstract

Helicobacter pylori is a spiral, gram-negative bacterium that specifically and persistently infects the human stomach. In some individuals, H. pylori-induced chronic gastritis may progress to gastroduodenal ulcers and gastric cancer. Currently, the host-microbe interactions that determine the clinical outcome of infection are not well defined. H. pylori strains capable of disrupting the gastric epithelial barrier may increase the likelihood of developing serious disease. In this study, H. pylori strain SS1 increased gastric, but not small intestinal, permeability in C57BL/6 mice. H. pylori strain SS1 was able to directly increase paracellular permeability, in the absence of host inflammatory cells, by disrupting the tight-junctional proteins occludin, claudin-4, and claudin-5 in confluent nontransformed epithelial cells. H. pylori SS1 also reduced claudin-4 protein levels in human gastric AGS cells. The ability of H. pylori SS1 to increase permeability appeared to be independent of the well-characterized virulence factors vacuolating cytotoxin and CagA protein. H. pylori activated myosin light-chain kinase in epithelial cells to phosphorylate myosin light chain and increase permeability by disrupting claudin-4 and claudin-5. The bacterial factor responsible for increasing epithelial permeability was heat sensitive, membrane bound, and required apical contact with monolayers. In conclusion, disruptions of the tight junctions observed in this study implicate host cell signaling pathways, including the phosphorylation of myosin light chain and the regulation of tight-junctional proteins claudin-4 and claudin-5, in the pathogenesis of H. pylori infection.

Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain

“…The early period of increased paracellular permeability of [ 14 C]sucrose (24 h) correlated with not only reduced claudin-5 expression, but also with a decrease in its co-localization with ZO-1. Similar to these presented data, increased permeability has also been linked to a loss of claudin-5 expression and movement away from the junction in gastric epithelium (Fedwick et al, 2005). During the later period of disruption in paracellular transport, claudin-5 co-localized with ZO-1, but was also visible in a discontinuous and non-junctional pattern throughout the endothelial cell (Figs.…”

Expression of tight-junction-associated proteins in human gastric cancer: downregulation of claudin-4 correlates with tumor aggressiveness and survival

“…For example, it has been reported that H. pylori was able to increase paracellular permeability by disrupting occludin, claudin-4, and claudin-5 [10], and Cdx2 was shown to play an important role in the regulation of intestinal claudin expression not only in gastric mucosa with intestinal metaplasia but also in gastric carcinoma [11]. Moreover, ALL-1 fusion partner from chromosome 6 (AF-6), which is a Ras target, interacts with ZO-1 [16,17].…”

“…To date, several studies have been reported regarding the biological functions of claudin-4 in gastric cancer. For example, it has been reported that Helicobacter pylori was able to increase paracellular permeability by disrupting occludin, claudin-4, and claudin-5 [10], and it has been shown that Cdx2 plays an important role in the regulation of intestinal claudin expression, not only…”

Roles of the Cyclooxygenase 2 Matrix Metalloproteinase 1 Pathway in Brain Metastasis of Breast Cancer

“…Metastatic tumor cells must first breach the blood-brain barrier (BBB), 3 which acts as a selective interface between the peripheral circulation and the central nervous system. BBB is a unique anatomical structure that is mainly constructed by tight junctions between the brain endothelial cells and pericytes that are embedded in the basement membrane of the endothelial cells (2)(3)(4)(5)(6)(7)(8). The tight junction confers low paracellular permeability and high electrical resistance, making the barrier function 50 -100 times tighter than peripheral microvessels (9).…”