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Am J Physiol Gastrointest Liver Physiol 281: G833-G847, 2001;
0193-1857/01 $5.00
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Vol. 281, Issue 3, G833-G847, September 2001

PKC-beta 1 mediates EGF protection of microtubules and barrier of intestinal monolayers against oxidants

A. Banan1, J. Z. Fields1, D. A. Talmage2, Yang Zhang1, and A. Keshavarzian1

1 Division of Digestive Diseases, Department of Internal Medicine, and Departments of Pharmacology and Molecular Physiology, Rush University Medical Center, Chicago, Illinois 60612; and 2 Institute of Human Nutrition, Columbia University, New York, New York 10032

Using monolayers of human intestinal (Caco-2) cells, we found that oxidants and ethanol damage the cytoskeleton and disrupt barrier integrity; epidermal growth factor (EGF) prevents damage by enhancement of protein kinase C (PKC) activity and translocation of the PKC-beta 1 isoform. To see if PKC-beta 1 mediates EGF protection, cells were transfected to stably over- or underexpress PKC-beta 1. Transfected monolayers were preincubated with low or high doses of EGF (1 or 10 ng/ml) or 1-oleoyl-2-acetyl-sn-glycerol [OAG; a PKC activator (0.01 or 50 µM)] before treatment with oxidant (0.5 mM H2O2). Only in monolayers overexpressing PKC-beta 1 (3.1-fold) did low doses of EGF or OAG initiate protection, increase tubulin polymerization (assessed by quantitative immunoblotting) and microtubule architectural integrity (laser scanning confocal microscopy), maintain normal barrier permeability (fluorescein sulfonic acid clearance), and cause redistribution of PKC-beta 1 from cytosolic pools into membrane and/or cytoskeletal fractions (assessed by immunoblotting), thus indicating PKC-beta 1 activation. Antisense inhibition of PKC-beta 1 expression (-90%) prevented these changes and abolished EGF protection. We conclude that EGF protection against oxidants requires PKC-beta 1 isoform activation. This mechanism may be useful for development of novel therapies for the treatment of inflammatory gastrointestinal disorders including inflammatory bowel disease.

tubulin; cytoskeleton; growth factors; paracellular permeability; fluorescein sulfonic acid clearance; Caco-2 cells; protein kinase C transfection, epidermal growth factor


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