C-terminal repeats of Clostridium difficile toxin a induce production of chemokine and adhesion molecules in endothelial cells and promote migration of leukocytes

Chiou Yueh Yeh, Chun Nan Lin, Chuan Fa Chang, Chun Hung Lin, Huei Ting Lien, Jen Yang Chen, Jean San Chia

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

The C-terminal repeating sequences of Clostridium difficile toxin A (designated ARU) are homologous to the carbohydrate-binding domain of streptococcal glucosyltransferases (GTFs) that were recently identified as potent modulins. To test the hypothesis that ARU might exert a similar biological activity on endothelial cells, recombinant ARU (rARU), which was noncytotoxic to cell cultures, was analyzed using human umbilical vein endothelial cells. The rARU could bind directly to endothelial cells in a serum- and calcium-dependent manner and induce the production of interleukin-6 (IL-6), IL-8, and monocyte chemoattractant protein 1 in a dose-dependent manner. An oligosaccharide binding assay indicated that rARU, but not GTFC, binds preferentially to Lewis antigens and 3′HSO3-containing oligosaccharides. Binding of rARU to human endothelial or intestinal cells correlated directly with the expression of Lewis Y antigen. Bound rARU directly activated mitogen-activated protein kinases and the NF-κB signaling pathway in endothelial cells to release biologically active chemokines and adhesion molecules that promoted migration in a transwell assay and the adherence of polymorphonuclear and mononuclear cells to the endothelial cells. These results suggest that ARU may bind to multiple carbohydrate motifs to exert its biological activity on human endothelial cells.

Original languageEnglish
Pages (from-to)1170-1178
Number of pages9
JournalInfection and Immunity
Volume76
Issue number3
DOIs
Publication statusPublished - 2008 Mar

All Science Journal Classification (ASJC) codes

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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