Nickel differentially regulates NFAT and NF-κB activation in T cell signaling

Nickel is a potent hapten that induces contact hypersensitivity in human skin. While nickel induces the maturation of dendritic cells via NF-κB and p38 MAPK activation, it also exerts immunosuppressive effects on T cells through an unknown mechanism. To elucidate the molecular mechanisms of its effects on T cells, we examined the effects of NiCl2 on mRNA expression in human CD3+ T cells stimulated with CD3 and CD28 antibodies. Using a DNA microarray and Gene Ontology, we identified 70 up-regulated (including IL-1β, IL-6 and IL-8) and 61 down-regulated (including IL-2, IL-4, IL-10 and IFN-γ) immune responsive genes in NiCl2-treated T cells. The DNA microarray results were verified using real-time PCR and a Bio-PlexTM suspension protein array. Suppression of IL-2 and IFN-γ gene transcription by NiCl2 was also confirmed using Jurkat T cells transfected with IL-2 or IFN-γ luciferase reporter genes. To explore the NiCl2-regulated signaling pathway, we examined the binding activity of nuclear proteins to NFAT, AP-1, and NF-κB consensus sequences. NiCl2 significantly and dose-dependently suppressed NFAT- and AP-1-binding activity, but augmented NF-κB-binding activity. Moreover, NiCl2 decreased nuclear NFAT expression in stimulated T cells. Using Jurkat T cells stimulated with PMA/ionomycin, we demonstrated that NiCl2 significantly suppressed stimulation-evoked cytosolic Ca2+ increases, suggesting that NiCl2 regulates NFAT signals by acting as a blocker of Ca2+ release-activated Ca2+ (CRAC) channels. These data showed that NiCl2 decreases NFAT and increases NF-κB signaling in T cells. These results shed light on the effects of nickel on the molecular regulation of T cell signaling.

Graphical AbstractNickel suppresses stimulation-evoked cytosolic Ca2+ increase, which results in the suppression of NFAT signals. On the other hand, Ni rather stimulates NF-κB signaling.The effects of Nickel on these transcription factors modulate the expression of various immune related genes.Figure optionsDownload high-quality image (160 K)Download as PowerPoint slideResearch highlights
► Using DNA microarray and Gene Ontology, we identified 70 up-regulated and 61 down-regulated immune responsive genes in NiCl2-treated T cells.
► NiCl2 significantly suppressed the binding activity of nuclear proteins from stimulated T cells to NFAT and AP-1 consensus binding sites, while it rather augmented that from non-stimulated T cells to NF-κB.
► NiCl2 significantly suppressed stimulation-evoked cytosolic Ca2+ increases, suggesting that NiCl2 regulates NFAT signals by acting as a blocker of CRAC channels.