title: Nickel differentially regulates NFAT and NF-κB activation in T cell signaling.
abstract: 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 NiCl(2) 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 NiCl(2)-treated T cells. The DNA microarray results were verified using real-time PCR and a Bio-Plex(TM) suspension protein array. Suppression of IL-2 and IFN-γ gene transcription by NiCl(2) was also confirmed using Jurkat T cells transfected with IL-2 or IFN-γ luciferase reporter genes. To explore the NiCl(2)-regulated signaling pathway, we examined the binding activity of nuclear proteins to NFAT, AP-1, and NF-κB consensus sequences. NiCl(2) significantly and dose-dependently suppressed NFAT- and AP-1-binding activity, but augmented NF-κB-binding activity. Moreover, NiCl(2) decreased nuclear NFAT expression in stimulated T cells. Using Jurkat T cells stimulated with PMA/ionomycin, we demonstrated that NiCl(2) significantly suppressed stimulation-evoked cytosolic Ca(2+) increases, suggesting that NiCl(2) regulates NFAT signals by acting as a blocker of Ca(2+) release-activated Ca(2+) (CRAC) channels. These data showed that NiCl(2) 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.
authors.affiliation: Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan.
authors.forename: Rumiko
authors.initials: R
authors.lastname: Saito
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirakawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohara
authors.forename: Makoto
authors.initials: M
authors.lastname: Yasuda
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nishii
authors.forename: Setsuya
authors.initials: S
authors.lastname: Aiba
mesh_terms: D000328:Adult; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D009532:Nickel / Q000494:pharmacology / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D055815:Young Adult
chemical_list: D016328:NF-kappa B; D050778:NFATC Transcription Factors; D009532:Nickel