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* Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany;
Institute of Experimental Dermatology, Interdisciplinary Center of Clinical Research, and Department of Pediatrics, and
Institute of Molecular Virology, University of Münster, Münster, Germany; and
Laboratory for Experimental Dermatology, Department of Dermatology and Venerology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany
Endothelial cells (EC) actively participate in the innate defense against microbial pathogens. Under unfavorable conditions, defense reactions can turn life threatening resulting in sepsis. We therefore studied the so far largely unknown EC reaction patterns to the fungal pathogen Candida albicans, which is a major cause of lethality in septic patients. Using oligonucleotide microarray analysis, we identified 56 genes that were transcriptionally up-regulated and 69 genes that were suppressed upon exposure of ECs to C. albicans. The most significantly up-regulated transcripts were found in gene ontology groups comprising the following categories: chemotaxis/migration; cell death and proliferation; signaling; transcriptional regulation; and cell-cell contacts/intercellular signaling. Further examination of candidate signaling cascades established a central role of the proinflammatory NF-
B pathway in the regulation of the Candida-modulated transcriptome of ECs. As a second major regulatory pathway we identified the stress-activated p38 MAPK pathway, which critically contributes to the regulation of selected Candida target genes such as CXCL8/IL-8. Depletion of MyD88 and IL-1R-associated kinase-1 by RNA interference demonstrates that Candida-induced NF-B activation is mediated by pattern recognition receptor signaling. Additional experiments suggest that C. albicans-induced CXCL8/IL-8 expression is mediated by TLR3 rather than TLR2 and TLR4, which previously have been implicated with MyD88/IB kinase-2/NF-B activation by this fungus in other systems. Our study provides the first comprehensive analysis of endothelial gene responses to C. albicans and presents novel insights into the complex signaling patterns triggered by this important pathogen.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants Go 811/1-5 (to M.G.), SFB293, A16 (to J.R.), and A17 (to S.L.) from the Deutsche Forschungsgemeinschaft, Grant Fö2/005/06 from the Interdisciplinary Clinical Research Centre of the University of Münster (to D.V.), Grant 95.064.3 from the Wilhelm Sander-Stiftung (to M.G.), and by Grant N2 OGU, TP6 from the Exzellenzförderung Sachsen-Anhalt (to M.L.).
2 Address correspondence and reprint requests to Dr. Matthias Goebeler, Department of Dermatology, University Hospital Medical Center, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68135 Mannheim, Germany, E-mail address: matthias.goebeler{at}haut.ma.uni-heidelberg.de
3 Abbreviations used in this paper: PRR, pattern recognition receptor; IKK, IB kinase; EC, endothelial cell; RNAi, RNA interference; shRNA, small hairpin RNA; siRNA, small interfering RNA; IRAK, IL-1R-associated kinase; poly(I:C), polyinosinic-polycytidylic acid; MOI, multiplicity of infection.
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