Down‐regulation of occludin expression in astrocytes by tumour necrosis factor (TNF) is mediated via TNF type‐1 receptor and nuclear factor‐κB activation

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Abstract
Tight junctions form the diffusion barrier of brain microcapillary endothelial cells and support cell polarity. Also astrocytes express tight junction components such as occludin, claudin‐1, ZO‐1 and ZO‐2, but do not establish a permeability barrier. However, little is known about the function and regulation of these molecules in astrocytes. We studied the impact of tumour necrosis factor (TNF) on occludin and ZO‐1 expression in astrocytes. TNF decreased occludin, but not ZO‐1 expression. In brain microcapillary endothelial cells, as well as in epithelial cells, occludin expression was not influenced by TNF. Removal of TNF from astrocytes restored the basal level of occludin. Down‐regulation was inhibited by caffeic acid phenethyl ester, a specific inhibitor of nuclear factor‐κB (NF‐κB) activation. Exposure of astrocytes isolated from mice deficient in either TNF type‐1 receptor (TNFR1), TNF type‐2 receptor (TNFR2), or both, respectively, revealed that down‐regulation was mediated entirely by TNFR1. ZO‐1, which can interact with occludin, was found to co‐precipitate connexin43, but not occludin. These findings demonstrate that TNF selectively down‐regulates occludin in astrocytes, but not in cells forming established tight junctions, through TNFR1 and suggest that NF‐κB is involved as a negative regulator.