Early cell signaling by the cytotoxic enterotoxin of Aeromonas hydrophila in macrophages

A cytotoxic enterotoxin (Act) of Aeromonas hydrophila is an important virulence factor with hemolytic, cytotoxic and enterotoxic activities. In this report, we demonstrated Act rapidly mobilized calcium from intracellular stores and evoked influx of calcium from the extracellular milieu in macrophag...

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Bibliographic Details
Published in:Microbial pathogenesis 2002-04, Vol.32 (4), p.149-163
Main Authors: Ribardo, D.A., Kuhl, K.R., Boldogh, I., Peterson, J.W., Houston, C.W., Chopra, A.K.
Format: Article
Language:English
Subjects:
Aeromonas hydrophila
Aeromonas hydrophila, cytotoxic enterotoxin, prostaglandin E2, tumor necrosis factor alpha, calcium mobilization, transcription factor NF-κB, reactive oxygen species
Bacterial Proteins
Bacteriology
Biological and medical sciences
Blotting, Western
Calcium - metabolism
Calcium Signaling - drug effects
Carbon-Oxygen Lyases - metabolism
Cell Line
Cytotoxins - pharmacology
Dinoprostone - metabolism
DNA-(Apurinic or Apyrimidinic Site) Lyase
Enterotoxins - pharmacology
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Fundamental and applied biological sciences. Psychology
Macrophages - drug effects
Macrophages - metabolism
Microbiology
NF-kappa B - metabolism
Oxidative Stress - drug effects
Pathogenicity, virulence, toxins, bacteriocins, pyrogens, host-bacteria relations, miscellaneous strains
Protein Kinases - metabolism
Reactive Oxygen Species - metabolism
Signal Transduction - drug effects
Tumor Necrosis Factor-alpha - metabolism
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Summary:A cytotoxic enterotoxin (Act) of Aeromonas hydrophila is an important virulence factor with hemolytic, cytotoxic and enterotoxic activities. In this report, we demonstrated Act rapidly mobilized calcium from intracellular stores and evoked influx of calcium from the extracellular milieu in macrophages. A direct role of calcium in Act-induced prostaglandin (e.g. PGE2) and tumor necrosis factor alpha (TNFα) production was demonstrated in macrophages using a cell-permeable calcium chelator BAPTA-AM, which also down-regulated activation of transcription factor NF-κB. We showed that Act's capacity to increase PGE2 and TNFα production could be blocked by inhibitors of tyrosine kinases and protein kinase A. In addition, Act caused up-regulation of the DNA repair enzyme redox factor-1 (Ref-1), which potentially could promote DNA binding of the transcription factors allowing modulation of various genes involved in the inflammatory response. Taken together, a link between Act-induced calcium release, regulation of downstream kinase cascades and Ref-1, and activation of NF-κB leading to PGE2 and TNFα production was established. Since Act also caused extensive tissue damage, we showed that Act increased reactive oxygen species, and the antioxidant N-acetyl cysteine, blocked Act-induced PGE2 and TNFα production, as well as NF-κB nuclear translocation in macrophages. We have demonstrated for the first time early cell signaling initiated in eukaryotic cells by Act, which leads to various biological effects associated with this toxin.
ISSN:0882-4010
1096-1208
DOI:10.1006/mpat.2001.0490