PMID- 22833676 OWN - NLM STAT- MEDLINE DCOM- 20121207 LR - 20211021 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 287 IP - 39 DP - 2012 Sep 21 TI - A disintegrin and metalloproteinase 17 (ADAM17) and epidermal growth factor receptor (EGFR) signaling drive the epithelial response to Staphylococcus aureus toxic shock syndrome toxin-1 (TSST-1). PG - 32578-87 AB - 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 alpha (TGFalpha), 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, TGFalpha, 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, TGFalpha, 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. FAU - Breshears, Laura M AU - Breshears LM AD - Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA. FAU - Schlievert, Patrick M AU - Schlievert PM FAU - Peterson, Marnie L AU - Peterson ML LA - eng GR - R01 AI073366/AI/NIAID NIH HHS/United States GR - R01 AI074283/AI/NIAID NIH HHS/United States GR - R01AI074283/AI/NIAID NIH HHS/United States GR - R01AI073366-03/AI/NIAID NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20120725 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (AREG protein, human) RN - 0 (Amphiregulin) RN - 0 (Bacterial Toxins) RN - 0 (CXCL8 protein, human) RN - 0 (Dipeptides) RN - 0 (EGF Family of Proteins) RN - 0 (Enterotoxins) RN - 0 (Glycoproteins) RN - 0 (Hydroxamic Acids) RN - 0 (Intercellular Signaling Peptides and Proteins) RN - 0 (Interleukin-8) RN - 0 (N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide) RN - 0 (Receptors, Tumor Necrosis Factor, Type I) RN - 0 (SDC1 protein, human) RN - 0 (Superantigens) RN - 0 (Syndecan-1) RN - 0 (Transforming Growth Factor alpha) RN - 0 (enterotoxin F, Staphylococcal) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 3.4.24.- (ADAM Proteins) RN - EC 3.4.24.86 (ADAM17 Protein) RN - EC 3.4.24.86 (ADAM17 protein, human) SB - IM MH - ADAM Proteins/genetics/*metabolism MH - ADAM17 Protein MH - Amphiregulin MH - Bacterial Toxins/genetics/*metabolism MH - Dipeptides/genetics/metabolism MH - EGF Family of Proteins MH - Enterotoxins/genetics/*metabolism MH - ErbB Receptors/genetics/*metabolism MH - Glycoproteins/genetics/metabolism MH - Human Umbilical Vein Endothelial Cells/*metabolism/pathology MH - Humans MH - Hydroxamic Acids/metabolism MH - Intercellular Signaling Peptides and Proteins/genetics/metabolism MH - Interleukin-8/genetics/metabolism MH - *Models, Biological MH - Receptors, Tumor Necrosis Factor, Type I/genetics/metabolism MH - *Signal Transduction MH - Staphylococcus aureus/genetics/*metabolism MH - Superantigens/genetics/*metabolism MH - Syndecan-1/genetics/metabolism MH - Transforming Growth Factor alpha/genetics/metabolism PMC - PMC3463354 EDAT- 2012/07/27 06:00 MHDA- 2012/12/12 06:00 PMCR- 2013/09/21 CRDT- 2012/07/27 06:00 PHST- 2012/07/27 06:00 [entrez] PHST- 2012/07/27 06:00 [pubmed] PHST- 2012/12/12 06:00 [medline] PHST- 2013/09/21 00:00 [pmc-release] AID - S0021-9258(20)62918-0 [pii] AID - M112.352534 [pii] AID - 10.1074/jbc.M112.352534 [doi] PST - ppublish SO - J Biol Chem. 2012 Sep 21;287(39):32578-87. doi: 10.1074/jbc.M112.352534. Epub 2012 Jul 25.