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TNF? alters occludin and cerebral endothelial permeability: Role of p38MAPK.


ABSTRACT: Occludin is a key tight junction (TJ) protein in cerebral endothelial cells (CECs) playing an important role in modulating blood-brain barrier (BBB) functions. This protein (65kDa) has been shown to engage in many signaling pathways and phosphorylation by both tyrosine and threonine kinases. Despite yet unknown mechanisms, pro-inflammatory cytokines and endotoxin (lipopolysaccharides, LPS) may alter TJ proteins in CECs and BBB functions. Here we demonstrate the responses of occludin in an immortalized human cerebral endothelial cell line (hCMEC/D3) to stimulation by TNF? (10 ng/mL), IL-1? (10 ng/mL) and LPS (100 ng/mL). Exposing cells to TNF? resulted in a rapid and transient upward band-shift of occludin, suggesting of an increase in phosphorylation. Exposure to IL-1? produced significantly smaller effects and LPS produced almost no effects on occludin band-shift. TNF? also caused transient stimulation of p38MAPK and ERK1/2 in hCMEC/D3 cells, and the occludin band-shift induced by TNF? was suppressed by SB202190, an inhibitor for p38MAPK, and partly by U0126, the MEK1/2-ERK1/2 inhibitor. Cells treated with TNF? and IL-1? but not LPS for 24 h resulted in a significant (p < 0.001) decrease in the expression of occludin, and the decrease could be partially blocked by SB202190, the inhibitor for p38MAPK. Treatment with TNF? also altered cell morphology and enhanced permeability of the CEC layer as measured by the FITC-dextran assay and the trans-endothelial electrical resistances (TEER). However, treatment with SB202190 alone could not effectively reverse the TNF? -induced morphology changes or the enhanced permeability changes. These results suggest that despite effects of TNF? on p38MAPK-mediated occludin phosphorylation and expression, these changes are not sufficient to avert the TNF?-induced alterations on cell morphology and permeability.

SUBMITTER: Ni Y 

PROVIDER: S-EPMC5295672 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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TNFα alters occludin and cerebral endothelial permeability: Role of p38MAPK.

Ni Yawen Y   Teng Tao T   Li Runting R   Simonyi Agnes A   Sun Grace Y GY   Lee James C JC  

PloS one 20170207 2


Occludin is a key tight junction (TJ) protein in cerebral endothelial cells (CECs) playing an important role in modulating blood-brain barrier (BBB) functions. This protein (65kDa) has been shown to engage in many signaling pathways and phosphorylation by both tyrosine and threonine kinases. Despite yet unknown mechanisms, pro-inflammatory cytokines and endotoxin (lipopolysaccharides, LPS) may alter TJ proteins in CECs and BBB functions. Here we demonstrate the responses of occludin in an immort  ...[more]

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