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Am J Physiol Gastrointest Liver Physiol 284: G703-G712, 2003. First published December 27, 2002; doi:10.1152/ajpgi.00214.2002
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Vol. 284, Issue 4, G703-G712, April 2003

Bryostatin-1 attenuates TNF-induced epithelial barrier dysfunction: role of novel PKC isozymes

James Yoo1, Anthony Nichols2, Jaekyung C. Song2, Joshua Mammen2, Isabel Calvo2, Roger T. Worrell2, John Cuppoletti2, Karl Matlin2, and Jeffrey B. Matthews2

1 Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215; and 2 Department of Surgery, University of Cincinnati Medical Center, Cincinnati, Ohio 45267

Tumor necrosis factor (TNF) increases epithelial permeability in many model systems. Protein kinase C (PKC) isozymes regulate epithelial barrier function and alter ligand-receptor interactions. We sought to define the impact of PKC on TNF-induced barrier dysfunction in T84 intestinal epithelia. TNF induced a dose- and time-dependent fall in transepithelial electrical resistance (TER) and an increase in [3H]mannitol flux. The TNF-induced fall in TER was not PKC mediated but was prevented by pretreatment with bryostatin-1, a PKC agonist. As demonstrated by a pattern of sensitivity to pharmacological inhibitors of PKC, this epithelial barrier preservation was mediated by novel PKC isozymes. Bryostatin-1 reduced TNF receptor (TNF-R1) surface availability, as demonstrated by radiolabeled TNF binding and cell surface biotinylation assays, and increased TNF-R1 receptor shedding. The pattern of sensitivity to isozyme-selective PKC inhibitors suggested that these effects were mediated by activation of PKC-epsilon . In addition, after bryostatin-1 treatment, PKC-delta and TNF-R1 became associated, as determined by mutual coimmunoprecipitation assay, which has been shown to lead to receptor desensitization in neutrophils. TNF-induced barrier dysfunction occurs independently of PKC, but selective modulation of novel PKC isozymes may regulate TNF-R1 signaling.

protein kinase C; tumor necrosis factor; epithelial barrier function


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