Effects of the Escherichia coli toxin cytolysin A on mucosal immunostimulation via epithelial Ca2+ signalling and Toll-like receptor 4.
2005 (English)In: Cell Microbiol, ISSN 1462-5814, Vol. 7, no 6, 779-88 p.Article in journal (Refereed) Published
Epithelial cells are vital to sense the presence of bacteria, thereby initiating a proper innate immune response. This occurs via different mechanisms, e.g. recognition by pattern recognition receptors (TLR), or alteration of the cellular Ca2+ homeostasis. The Escherichia coli toxin cytolysin A (ClyA) is naturally delivered to target cells as active pore assemblies within outer membrane vesicles (OMVs), and we here investigate a possible role of ClyA-containing OMVs (ClyA+ (OMV)) for induction of proinflammatory responses via the above-mentioned mechanisms. We report that low, sublytic concentrations of ClyA+ (OMV) affect the Ca2+ homeostasis in epithelial cells by induction of slow, intracellular Ca2+ oscillations, while increased concentrations act cytolytically. Thus, ClyA belongs to the novel group of pore-forming toxins shown to elicit such biphasic responses. Ca2+ waves in the minute range have been shown to regulate gene transcription of, e.g. interleukin (IL)-6 and -8. While the periodicity of ClyA+ (OMV)-induced Ca2+ waves (22.9 +/- 0.9 min) fail to induce an IL-8 response, our data fit to the general concept of frequency-specific gene expression. Molecular investigations of the signal transduction pathway reveals that ClyA+ (OMV) utilize a different one as compared with those previously reported for other toxins causing Ca2+ waves. The ClyA protein per se and ClyA pore assemblies are non-immunogenic, while lipopolysaccharide present on the OMVs induces a TLR4-dependent proinflammatory response as expected. Additional membrane components of the OMV, e.g. OmpW, was also found to elicit proinflammatory responses that was independent of TLR4 and Ca2+ signalling.
Place, publisher, year, edition, pages
2005. Vol. 7, no 6, 779-88 p.
Animals, Bacterial Outer Membrane Proteins/immunology, Calcium/metabolism, Calcium Signaling, Cells; Cultured, Epithelial Cells/*immunology/microbiology, Escherichia coli/immunology, Escherichia coli Proteins/immunology/*metabolism, Female, Hemolysin Proteins/*metabolism, Humans, Immunity; Mucosal, Immunity; Natural, Interleukin-6/metabolism, Interleukin-8/metabolism, Lipopolysaccharides/toxicity, Membrane Glycoproteins/*physiology, Rats, Rats; Sprague-Dawley, Receptors; Cell Surface/*physiology, Second Messenger Systems, Signal Transduction, Toll-Like Receptor 4, Toll-Like Receptors
IdentifiersURN: urn:nbn:se:umu:diva-16636PubMedID: 15888081OAI: oai:DiVA.org:umu-16636DiVA: diva2:156309