Abstract
Meprins are metalloproteinases that cleave a range of biologically important substrates such as extracellular matrix proteins, adherens junction proteins, and cytokines. Previous studies in our laboratory showed that disruption of the meprin A gene leads to altered outcomes of mouse models of inflammatory bowel diseases and endotoxin‐induced inflammation. Because disruption of epithelial cell interaction can contribute to inflammatory responses, the influence of mouse homomeric meprin A on the function of epithelial barrier has been explored. Cultured Madin‐Darby canine kidney (MDCK) cells exposed to active homomeric meprin A show decreased immunostaining for ZO‐1 and occludin in the tight junction of the confluent cell layer. Monolayers of MDCK cells incubated with active meprin A, but not latent meprin A, display decreased transepithelial electrical resistance and increased permeability to fluorescein‐5‐isothiocyanate (FITC)‐labeled dextran. The tight junction protein occludin, but not claudin‐4 is cleaved by meprin A in both membrane‐enriched cell fractions and intact monolayers of MDCK cells. These results indicate that meprin A impairs the integrity of epithelial barriers and selectively cleaves tight junction proteins, thereby affecting leukocyte migration and/or cytokines accumulation at sites of inflammation.
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