Abstract
Staphylococcal superantigens (SAgs), such as toxic shock syndrome toxin-1 (TSST-1), are the main cause of toxic shock syndrome (TSS). SAgs deregulate the host immune system after penetrating epithelial barriers such as the vaginal mucosa. In response to TSST-1, human vaginal epithelial cells (HVECs) produce cytokines and undergo morphological changes. The epithelial signaling mechanisms employed by SAgs remain largely unknown and are the focus of the work presented here. Analysis of published microarray data identified a network of genes up-regulated by HVECs in response to TSST-1 that includes the sheddase, a disintegrin and metalloproteinase 17 (ADAM17). Investigation revealed that the ADAM17 proteolytic targets, amphiregulin (AREG), transforming growth factor α (TGFα), syndecan-1 (SDC1), and tumor necrosis factor receptor 1 (TNFR1), are shed from HVECs in response to TSST-1. TAPI-1 (an ADAM inhibitor) completely abrogates all observed shedding and the production of the cytokine interleukin-8 (IL-8). Knock-down studies show that ADAM17, but not the closely related ADAM10, is required for AREG, TGFα, and TNFR1 shedding. Both ADAM10 and ADAM17 contribute to SDC1 shedding and IL-8 production by HVECs in response to TSST-1. EGFR signaling is critical for up-regulation of IL-8 at the transcriptional level in response to TSST-1 and is also necessary for AREG, TGFα, and TNFR1 shedding. A model is proposed describing the interactions of TSST-1, ADAMs, and the EGFR that lead to establishment of a proinflammatory positive feedback loop in epithelial cells and demonstrate a role for SAgs in the initial stages of disease.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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ADAM Proteins / genetics
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ADAM Proteins / metabolism*
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ADAM17 Protein
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Amphiregulin
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Bacterial Toxins / genetics
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Bacterial Toxins / metabolism*
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Dipeptides / genetics
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Dipeptides / metabolism
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EGF Family of Proteins
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Enterotoxins / genetics
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Enterotoxins / metabolism*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Glycoproteins / genetics
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Glycoproteins / metabolism
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Human Umbilical Vein Endothelial Cells / metabolism*
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Human Umbilical Vein Endothelial Cells / pathology
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Humans
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Hydroxamic Acids / metabolism
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Interleukin-8 / genetics
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Interleukin-8 / metabolism
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Models, Biological*
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Receptors, Tumor Necrosis Factor, Type I / genetics
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Signal Transduction*
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Staphylococcus aureus / genetics
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Staphylococcus aureus / metabolism*
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Superantigens / genetics
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Superantigens / metabolism*
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Syndecan-1 / genetics
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Syndecan-1 / metabolism
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Transforming Growth Factor alpha / genetics
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Transforming Growth Factor alpha / metabolism
Substances
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AREG protein, human
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Amphiregulin
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Bacterial Toxins
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CXCL8 protein, human
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Dipeptides
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EGF Family of Proteins
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Enterotoxins
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Glycoproteins
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Hydroxamic Acids
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Intercellular Signaling Peptides and Proteins
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Interleukin-8
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N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide
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Receptors, Tumor Necrosis Factor, Type I
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SDC1 protein, human
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Superantigens
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Syndecan-1
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Transforming Growth Factor alpha
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enterotoxin F, Staphylococcal
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EGFR protein, human
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ErbB Receptors
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ADAM Proteins
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ADAM17 Protein
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ADAM17 protein, human