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

James Yoo, Anthony Nichols, Jaekyung C. Song, Joshua Mammen, Isabel Calvo, Roger T. Worrell, John Cuppoletti, Karl Matlin, Jeffrey B. Matthews

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

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-ε. In addition, after bryostatin-1 treatment, PKC-δ 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.

Original languageEnglish (US)
Pages (from-to)G703-G712
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume284
Issue number4 47-4
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Keywords

  • Epithelial barrier function
  • Protein kinase C
  • Tumor necrosis factor

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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