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.

Statement of significance: 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.

Keywords: Human monocytes; Microarray analysis; Nickel; Pathways; Transcriptome.