Increased intestinal permeability by exogenous sphingomyelinase

Many signaling molecules involved in the pathogenesis of IBD, such as TNF or IFN, infections with bacteria or viruses and ionizing radiation, may cause an alteration of the lipid composition in the cell membrane by activation of sphingomyelinases (SMases).

Activation of SMases is followed by rapid hydrolysis of plasma membrane sphingomyelin to the sphingolipid ceramide.

Permeability of the intestinal mucosa is controlled by a complex of proteins and lipids between cells, which is commonly described as tight-junction (TJ). TJs are rich in sphingomyelin and thus, the researchers hypothesized that hydrolysis of sphingomyelin to ceramide changes the composition of TJs and increases permeability of the intestinal epithelium.

To test this hypothesis, a research group led by Dr. Bock at University of Regensburg in Germany investigated the permeability of cell monolayers of intestinal epithelial cells with an in vitro model of the epithelial barrier. The addition of exogenous sphingomyelinase to the monolayers increased transepithelial permeability even at very low concentrations. Lipid analysis showed rapid accumulation of ceramide and a decrease in sphingomyelin and cholesterol in the membrane fractions containing TJ-proteins. Immunofluorescent staining confirmed clustering of ceramide at the sites of cell/cell contacts. Treatment of the monolayers with an anti-ceramide antibody prevented an increase of permeability by platelet activating factor, which is a lipid messenger known to increase permeability.

These findings indicate that SMase leads to localized accumulation of ceramide at the sites of cell/cell-contact with increased intestinal permeability. These changes could explain early disturbances of the epithelial barrier upon cellular stress deriving from toxic, infectious, inflammatory or radiogenic challenge to the intestinal epithelium.

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