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inhibition prevents EGF protection of
intestinal cytoskeleton and barrier against oxidants
Division of Digestive Diseases, Department of Internal Medicine, and Departments of Pharmacology and Molecular Physiology, Rush University Medical Center, Chicago, Illinois 60612
Loss of intestinal
barrier integrity is associated with oxidative inflammatory GI
disorders including inflammatory bowel disease. Using monolayers of
human intestinal epithelial (Caco-2) cells, we recently
reported that epidermal growth factor (EGF) protects barrier
integrity against oxidants by stabilizing the microtubule cytoskeleton,
but the mechanism downstream of the EGF receptor (EGFR) is not
established. We hypothesized that phospholipase C (PLC)-
is
required. Caco-2 monolayers were exposed to oxidant (H2O2) with or without pretreatment with EGF or
specific inhibitors of EGFR tyrosine kinase (AG-1478, tyrphostin 25) or
of PLC (L-108, U-73122). Other Caco-2 cells were stably transfected
with a dominant negative fragment for PLC- (PLCz) to inhibit PLC-
activation. Doses of EGF that enhanced PLC activity also protected
monolayers against oxidant-induced tubulin disassembly, disruption of
the microtubule cytoskeleton, and barrier leakiness as assessed by radioimmunoassay, quantitative Western blots, high-resolution laser
confocal microscopy, and fluorometry, respectively.
Pretreatment with either type of inhibitor abolished EGF protection.
Transfected cells also lost EGF protection and showed reduced PLC-
phosphorylation and activity. We conclude that EGF protection requires
PLC- signaling and that PLC- may be a useful therapeutic target.
phospholipase Cz transfection; tubulin; epidermal growth factor; barrier integrity; Caco-2 cells
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