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The Contact Allergen Nickel Triggers a Unique Inflammatory and Proangiogenic Gene Expression Pattern via Activation of NF-B and Hypoxia-Inducible Factor-1¹

Dorothee Viemann^*, Marc Schmidt, Klaus Tenbrock^*, Sybille Schmid, Verena Müller, Kerstin Klimmek^*, Stephan Ludwig, Johannes Roth^* and Matthias Goebeler^2,

^* Institute of Experimental Dermatology, Interdisciplinary Center of Clinical Research, and Department of Pediatrics, University of Münster, Münster, Germany; Department of Dermatology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany; and Institute of Molecular Virology, University of Münster, Münster, Germany

Nickel compounds are prime inducers of contact allergy reactions in humans. To identify the signal transduction pathways mediating the cellular responses to nickel and to elucidate their hierarchy, we performed Affymetrix gene profiling using human primary endothelial cells, which strongly respond to nickel stimulation. Overall, we found 258 significantly modulated transcripts, comprising 140 up-regulated and 118 down-regulated genes. The bulk of those genes were identified as targets of two distinct signaling cascades, the IKK2/NF-B pathway and a proangiogenic pathway mediated by HIF-1, which accumulates upon exposure to nickel. Using dominant-interfering mutants and retroviral RNA interference technology, we demonstrate that both pathways act independently to regulate expression of nonoverlapping gene pools. NF-B activation mediates most of the proinflammatory responses to nickel. Nickel-dependent HIF-1 activation primarily modulates expression of genes involved in proliferation, survival, metabolism, and signaling, albeit the induction of some proinflammatory nickel-response genes, most prominently IL-6, which we identified as novel bona fide HIF-1 target in this study, is also critically dependent on this pathway. Furthermore, we provide evidence that transactivation of both transcription factors partially depends on p38 MAPK activation that contributes to the intensity of at least some target genes. Taken together, our data provide mechanistic insight into the complex network of nickel-induced cellular events and identify IKK2/NF-B and HIF-1 as important pathways involved in processes such as delivery of "second signals" in contact hypersensitivity reactions to nickel.

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 is supported by the Deutsche Forschungsgemeinschaft Grants Go 811/1-5 (to M.G.), SFB293, A16 (to J.R.), and A17 (to S.L.) and Interdisciplinary Clinical Research Centre of the University of Münster Grant Fö2/005/06 (to D.V.).

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: EC, endothelial cell; ChIP, chromatin immunoprecipitation; dn, dominant negative; dnHIF-1, dn mutant of HIF-1; HIF-1, hypoxia-inducible transcription factor-1; HRE, hypoxia-responsive element; IKK2kd, kinase-dead IKK2; qRT-PCR, quantitative real-time RT-PCR; PCA, principal component analysis; shRNA, small hairpin RNA; VEGF, vascular endothelial growth factor.

⁴ The online version of this article contains supplemental material.

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