The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha.
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-kappaB pathway and a proangiogenic pathway mediated by HIF-1alpha, 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-kappaB activation mediates most of the proinflammatory responses to nickel. Nickel-dependent HIF-1alpha 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-1alpha 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-kappaB and HIF-1alpha as important pathways involved in processes such as delivery of "second signals" in contact hypersensitivity reactions to nickel.
Viemann
Dorothee
D
Institute of Experimental Dermatology, Interdisciplinary Center of Clinical Research, and Department of Pediatrics, University of Münster, Münster, Germany.
Schmidt
Marc
M
Tenbrock
Klaus
K
Schmid
Sybille
S
Müller
Verena
V
Klimmek
Kerstin
K
Ludwig
Stephan
S
Roth
Johannes
J
Goebeler
Matthias
M
D000485:Allergens / Q000633:toxicity*; D017449:Dermatitis, Allergic Contact / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000276:immunology*; D018836:Inflammation Mediators / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000276:immunology*; D009532:Nickel / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D000485:Allergens; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D016328:NF-kappa B; D009532:Nickel; D048051:p38 Mitogen-Activated Protein Kinases