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B in the Clostridium difficile Toxin A-Induced Up-Regulation and Secretion of IL-8 from Human Monocytes1
Departments of
*
Medicine and
Microbiology, Health Sciences Center, University of Virginia, Charlottesville, VA 22908
Clostridium difficile causes an intense inflammatory
colitis through the actions of two large exotoxins, toxin A and toxin
B. IL-8 is believed to play an important role in the pathophysiology of
C. difficile-mediated colitis, although the mechanism
whereby the toxins up-regulate the release of IL-8 from target cells is
not well understood. In this study, we investigated the mechanisms
through which toxin A induces IL-8 secretion in human monocytes. We
found that cellular uptake of toxin A is required for the up-regulation
of IL-8, an effect that is not duplicated by a recombinant toxin
fragment comprising the cell-binding domain alone. Toxin A induced IL-8
expression at the level of gene transcription and this effect occurred
through a mechanism requiring intracellular calcium and calmodulin
activation. Additionally, the effects of toxin A were inhibited by the
protein tyrosine kinase inhibitor genistein, but were unaffected by
inhibitors of protein kinase C and phosphatidylinositol-3 kinase. We
determined that toxin A activates nuclear translocation of the
transcription factors NF-
B and AP-1, but not NF-IL-6. NF-B
inhibitors blocked the ability of toxin A to induce IL-8 secretion, and
supershift analysis indicated that the major isoform of NF-B
activated by the toxin is a p50-p65 heterodimer. This study is the
first to identify intracellular signaling pathways and transcription
factors involved in the C. difficile toxin-mediated
up-regulation of IL-8 synthesis and release by target cells. This
information should increase our understanding of the pathogenesis of
C. difficile colitis and the nature of IL-8 gene regulation
as well.
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