{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T17:52:15Z","timestamp":1790617935411,"version":"4.1.0"},"reference-count":40,"publisher":"American Society of Hematology","issue":"4","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2003,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Enterohemorrhagic Escherichia coli (EHEC) is the major cause of hemolyticuremic syndrome (HUS) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. EHEC produces one or more Shiga toxins (Stx1 and Stx2), and it was assumed that Stx's only relevant biologic activity was cell destruction through inhibition of protein synthesis. However, recent data indicate that in vivo the cytokine milieu may determine whether endothelial cells survive or undergo apoptosis\/necrosis when exposed to Stxs. In this study, we analyzed the genome-wide expression patterns of human endothelial cells stimulated with subinhibitory concentrations of Stxs in order to characterize the genomic expression program involved in the vascular pathology of HUS. We found that Stxs elicited few, but reproducible, changes in gene expression. The majority of genes reported in this study encodes for chemokines and cytokines, which might contribute to the multifaceted inflammatory response of host endothelial cells observed in patients suffering from EHEC disease. In addition, our data provide for the first time molecular insights into the epidemiologically well-established higher pathogenicity of Stx2 over Stx1.<\/jats:p>","DOI":"10.1182\/blood-2002-10-3301","type":"journal-article","created":{"date-parts":[[2003,4,22]],"date-time":"2003-04-22T00:14:56Z","timestamp":1050970496000},"page":"1323-1332","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":93,"title":["Molecular and functional analysis of Shiga toxin\u2013induced response patterns in human vascular endothelial cells"],"prefix":"10.1182","volume":"102","author":[{"given":"Andreas","family":"Matussek","sequence":"first","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joerg","family":"Lauber","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Bergau","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wiebke","family":"Hansen","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manfred","family":"Rohde","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt E. J.","family":"Dittmar","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Gunzer","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Mengel","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Gatzlaff","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maike","family":"Hartmann","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Buer","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florian","family":"Gunzer","sequence":"additional","affiliation":[{"name":"From the Mucosal Immunity Group, the Department of Microbiology, and the Department of Molecular Biotechnology, German Research Centre for Biotechnology (GBF), Braunschweig, Germany; the Institute of Medical Microbiology, Hannover Medical School, Hannover, Germany; the Department of Dermatology, University of Muenster, Muenster, Germany; and the Institute of Pathology, Hannover Medical School, Hannover, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2020021219283493300_REF1","doi-asserted-by":"crossref","unstructured":"Paton AW, Ratcliff RM, Doyle RM, et al. 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Heptinstall\u2032s Pathology of the Kidney. Philadelphia, PA: Lippincott-Raven Publishers; 1998: 1003-1057."},{"key":"2020021219283493300_REF8","doi-asserted-by":"crossref","unstructured":"Acheson DW, Moore R, De Breucker S, et al. Translocation of Shiga toxin across polarized intestinal cells in tissue culture. Infect Immun.1996;64: 3294-3300.","DOI":"10.1128\/IAI.64.8.3294-3300.1996"},{"key":"2020021219283493300_REF9","doi-asserted-by":"crossref","unstructured":"Endo Y, Tsurugi K, Yutsudo T, et al. Site of action of a Vero toxin (VT2) from Escherichia coli O157:H7 and of Shiga toxin on eukaryotic ribosomes: RNA N-glycosidase activity of the toxins. Eur J Biochem.1988;171: 45-50.","DOI":"10.1111\/j.1432-1033.1988.tb13756.x"},{"key":"2020021219283493300_REF10","doi-asserted-by":"crossref","unstructured":"Thorpe CM, Smith WE, Hurley BP, Acheson DW. 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