Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro

J Clin Invest. 1995 Aug;96(2):710-20. doi: 10.1172/JCI118114.

Abstract

The intracellular signaling involved in the mechanism of action of zonula occludens toxin (ZOT) was studied using several in vitro and ex vivo models. ZOT showed a selective effect among various cell lines tested, suggesting that it may interact with a specific receptor, whose surface expression on various cells differs. When tested in IEC6 cell monolayers, ZOT-containing supernatants induced a redistribution of the F-actin cytoskeleton. Similar results were obtained with rabbit ileal mucosa, where the reorganization of F-actin paralleled the increase in tissue permeability. In endothelial cells, the cytoskeletal rearrangement involved a decrease of the soluble G-actin pool (-27%) and a reciprocal increase in the filamentous F-actin pool (+22%). This actin polymerization was time- and dose-dependent, and was reversible. Pretreatment with a specific protein kinase C inhibitor, CGP41251, completely abolished the ZOT effects on both tissue permeability and actin polymerization. In IEC6 cells ZOT induced a peak increment of the PKC-alpha isoform after 3 min incubation. Taken together, these results suggest that ZOT activates a complex intracellular cascade of events that regulate tight junction permeability, probably mimicking the effect of physiologic modulator(s) of epithelial barrier function.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actins / metabolism*
  • Adenosine Triphosphatases / pharmacology*
  • Alkaloids / pharmacology
  • Animals
  • Carcinoma / pathology
  • Cattle
  • Cell Line
  • Cholera Toxin / pharmacology*
  • Colonic Neoplasms / pathology
  • Cytoskeleton / drug effects*
  • Cytoskeleton / metabolism
  • Cytoskeleton / ultrastructure
  • Endothelium, Vascular / drug effects
  • Humans
  • Ileum / drug effects
  • Intercellular Junctions / drug effects*
  • Intestinal Mucosa / drug effects
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / physiology
  • Kidney Cortex
  • Male
  • Organ Specificity
  • Permeability / drug effects
  • Phosphatidylinositol Diacylglycerol-Lyase
  • Phosphoric Diester Hydrolases / physiology
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / physiology*
  • Pulmonary Artery
  • Rabbits
  • Rats
  • Signal Transduction*
  • Species Specificity
  • Staurosporine
  • Swine
  • Tumor Cells, Cultured
  • Vibrio cholerae / physiology

Substances

  • Actins
  • Alkaloids
  • Isoenzymes
  • zonula occludens toxin, Vibrio cholerae
  • Cholera Toxin
  • Protein Kinase C
  • Phosphoric Diester Hydrolases
  • Adenosine Triphosphatases
  • Phosphatidylinositol Diacylglycerol-Lyase
  • Staurosporine
  • midostaurin