title: Genome-wide transcriptome induced by nickel in human monocytes.
abstract: Nickel-containing alloys are frequently used in the biomedical field, although, owing to corrosive processes metal ion leaching is inevitable. Due to nickel ion (Ni(2+)) leaching several adverse effects are described in the literature. However, only a few studies evaluated the genetic profile of Ni(2+) in human cells which is of great importance since nickel-induced effects differ between humans and mice as a result of species-specific receptor variability. Thus, we investigated gene expression induced by Ni(2+)in human monocytes using a transcriptome-wide approach determining new target genes implicated in nickel-induced pathologies. Monocytes were isolated from healthy volunteers of Central European origin using stringent inclusion criteria. Cells were challenged with different Ni(2+) concentrations. Array-based gene expression analysis was performed comprising more than 47,000 transcripts followed by pathway analyses. Transcriptional data were validated by protein and cell surface markers. Ni(2+) significantly influenced the expression of 1385 transcripts in a dose-dependent manner. Apart from known targets (CCL20↑, PTGS2↑, MTs↑, SLCs↑), we identified new candidates implicated in Ni(2+)-elicited processes (various microRNAs↑, INSIG1↑, NAMPT↑, MS4A6A↓, DHRS9↓). Several of these transcripts correspond to immunity, inflammation and were shown to be involved in cellular reactions related to hypersensitivity, cancer, colitis, and encephalitis. Moreover, 459 canonical pathways/signaling, 500 pathologies and 2687 upstream regulators were detected. Protein results validated our findings. To our knowledge, the present systematic transcriptome-wide expression study is the first which explored Ni(2+)-elicited cell responses in human primary monocytes identifying new target genes, pathways and upstream regulators of relevance to diagnostic and therapeutic strategies.
  
  
  
  Nickel is widely applied in the biomedical field, although several adverse effects are documented in the literature due to nickel ion (Ni(2+)) leaching. In humans, allergic reactions like contact dermatitis are the most common adverse effect to Ni(2+), whereas serious concerns relate to possible systemic and carcinogenic activities. Using a systematic genome-wide transcriptional approach in human primary monocytes unveil new target genes, pathways and upstream regulators implicated in nickel-elicited immune response which are of significance to diagnostic and therapeutic strategies. This approach provides new information of how host-derived immune response contributes to the interaction with antigens and supports the interplay between metal ions and systemic diseases.
authors.affiliation: Center of Dento-Maxillo-Facial Medicine, University Hospital of Bonn, Bonn 53111, Germany. Electronic address: lgoelz@uni-bonn.de.
authors.forename: Lina
authors.initials: L
authors.lastname: Gölz
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn 53127, Germany.
authors.forename: Benedikt C
authors.initials: BC
authors.lastname: Buerfent
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn 53127, Germany; Institute of Human Genetics, University Hospital of Bonn, Bonn 53127, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital of Bonn, Bonn 53127, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Rühl
authors.affiliation: Institute of Human Genetics, University Hospital of Bonn, Bonn 53127, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Fricker
authors.affiliation: Center of Dento-Maxillo-Facial Medicine, University Hospital of Bonn, Bonn 53111, Germany; Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn 53127, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Stamminger
authors.affiliation: Institute of Experimental Hematology and Transfusion Medicine, University Hospital of Bonn, Bonn 53127, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Oldenburg
authors.affiliation: Center of Dento-Maxillo-Facial Medicine, University Hospital of Bonn, Bonn 53111, Germany.
authors.forename: James
authors.initials: J
authors.lastname: Deschner
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn 53127, Germany; German Centre for Infection Research (DZIF), Partner site Bonn-Cologne, Bonn, Germany.
authors.forename: Achim
authors.initials: A
authors.lastname: Hoerauf
authors.affiliation: Institute of Human Genetics, University Hospital of Bonn, Bonn 53127, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: Institute of Human Genetics, University Hospital of Bonn, Bonn 53127, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schumacher
authors.affiliation: Institute of Medical Microbiology, Immunology and Parasitology, University Hospital of Bonn, Bonn 53127, Germany.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Hübner
authors.affiliation: Center of Dento-Maxillo-Facial Medicine, University Hospital of Bonn, Bonn 53111, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jäger
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D018925:Chemokines / Q000378:metabolism; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009532:Nickel / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D018925:Chemokines; D018950:Lipopolysaccharide Receptors; D012333:RNA, Messenger; D009532:Nickel
keywords: Human monocytes; Microarray analysis; Nickel; Pathways; Transcriptome