{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:33:37Z","timestamp":1791405217752,"version":"4.3.3"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2007,3,1]],"date-time":"2007-03-01T00:00:00Z","timestamp":1172707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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-\u03baB pathway and a proangiogenic pathway mediated by HIF-1\u03b1, 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-\u03baB activation mediates most of the proinflammatory responses to nickel. Nickel-dependent HIF-1\u03b1 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\u03b1 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-\u03baB and HIF-1\u03b1 as important pathways involved in processes such as delivery of \u201csecond signals\u201d in contact hypersensitivity reactions to nickel.<\/jats:p>","DOI":"10.4049\/jimmunol.178.5.3198","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T13:14:39Z","timestamp":1397826879000},"page":"3198-3207","source":"Crossref","is-referenced-by-count":72,"title":["The Contact Allergen Nickel Triggers a Unique Inflammatory and Proangiogenic Gene Expression Pattern via Activation of NF-\u03baB and Hypoxia-Inducible Factor-1\u03b1"],"prefix":"10.1093","volume":"178","author":[{"given":"Dorothee","family":"Viemann","sequence":"first","affiliation":[{"name":"Institute of Experimental Dermatology, Interdisciplinary Center of Clinical Research, and Department of Pediatrics, University of Mu\u0308nster , Mu\u0308nster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center Mannheim, University of Heidelberg , Mannheim ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Tenbrock","sequence":"additional","affiliation":[{"name":"Institute of Experimental Dermatology, Interdisciplinary Center of Clinical Research, and Department of Pediatrics, University of Mu\u0308nster , Mu\u0308nster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sybille","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center Mannheim, University of Heidelberg , Mannheim ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Mu\u0308ller","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center Mannheim, University of Heidelberg , Mannheim ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Klimmek","sequence":"additional","affiliation":[{"name":"Institute of Experimental Dermatology, Interdisciplinary Center of Clinical Research, and Department of Pediatrics, University of Mu\u0308nster , Mu\u0308nster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Institute of Molecular Virology, University of Mu\u0308nster , Mu\u0308nster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Roth","sequence":"additional","affiliation":[{"name":"Institute of Experimental Dermatology, Interdisciplinary Center of Clinical Research, and Department of Pediatrics, University of Mu\u0308nster , Mu\u0308nster ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Goebeler","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Medical Center Mannheim, University of Heidelberg , Mannheim ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2007,3,1]]},"reference":[{"key":"2026012810523407300_R1","first-page":"67","volume-title":"Mutat. 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