Nickel differentially regulates NFAT and NF-{kappa}B activation in T cell signaling

Journal Article · Mon Aug 01 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.04.017· OSTI ID:21587799

Saito, Rumiko ^[1]; Hirakawa, Satoshi ^[1]; Ohara, Hiroshi ^[2]; Yasuda, Makoto; Yamazaki, Tomomi; Nishii, Shigeaki ^[3]; Aiba, Setsuya ^[1]

---

1. Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai 980-8574 (Japan)
2. Department of Clinical Pharmacy, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8574 (Japan)
3. Tsuruga Institute of Biotechnology, TOYOBO Co., Ltd., Tsuruga 914-0047 (Japan)

Nickel is a potent hapten that induces contact hypersensitivity in human skin. While nickel induces the maturation of dendritic cells via NF-{kappa}B 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{sub 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-1{beta}, IL-6 and IL-8) and 61 down-regulated (including IL-2, IL-4, IL-10 and IFN-{gamma}) immune responsive genes in NiCl{sub 2}-treated T cells. The DNA microarray results were verified using real-time PCR and a Bio-Plex{sup TM} suspension protein array. Suppression of IL-2 and IFN-{gamma} gene transcription by NiCl{sub 2} was also confirmed using Jurkat T cells transfected with IL-2 or IFN-{gamma} luciferase reporter genes. To explore the NiCl{sub 2}-regulated signaling pathway, we examined the binding activity of nuclear proteins to NFAT, AP-1, and NF-{kappa}B consensus sequences. NiCl{sub 2} significantly and dose-dependently suppressed NFAT- and AP-1-binding activity, but augmented NF-{kappa}B-binding activity. Moreover, NiCl{sub 2} decreased nuclear NFAT expression in stimulated T cells. Using Jurkat T cells stimulated with PMA/ionomycin, we demonstrated that NiCl{sub 2} significantly suppressed stimulation-evoked cytosolic Ca{sup 2+} increases, suggesting that NiCl{sub 2} regulates NFAT signals by acting as a blocker of Ca{sup 2+} release-activated Ca{sup 2+} (CRAC) channels. These data showed that NiCl{sub 2} decreases NFAT and increases NF-{kappa}B signaling in T cells. These results shed light on the effects of nickel on the molecular regulation of T cell signaling. - Graphical Abstract: Nickel suppresses stimulation-evoked cytosolic Ca{sup 2+} increase, which results in the suppression of NFAT signals. On the other hand, Ni rather stimulates NF-{kappa}B signaling. The effects of Nickel on these transcription factors modulate the expression of various immune related genes. Display Omitted Research Highlights: > Using DNA microarray and Gene Ontology, we identified 70 up-regulated and 61 down-regulated immune responsive genes in NiCl{sub 2}-treated T cells. > NiCl{sub 2} 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-{kappa}B. > NiCl{sub 2} significantly suppressed stimulation-evoked cytosolic Ca{sup 2+} increases, suggesting that NiCl{sub 2} regulates NFAT signals by acting as a blocker of CRAC channels.

• OSTI ID: 21587799
• Journal Information: Toxicology and Applied Pharmacology, Vol. 254, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.04.017; PII: S0041-008X(11)00166-9; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANTIBODIES
CALCIUM IONS
DNA
DOSES
GENES
LEUKOCYTES
LIGANDS
LUCIFERASE
MACROPHAGES
MESSENGER-RNA
NICKEL
NICKEL CHLORIDES
POLYMERASE CHAIN REACTION
RECEPTORS
SIGNALS
SKIN
STIMULATION
TRANSCRIPTION FACTORS
ANIMAL CELLS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BODY
BODY FLUIDS
CHARGED PARTICLES
CHLORIDES
CHLORINE COMPOUNDS
CONNECTIVE TISSUE CELLS
ELEMENTS
ENZYMES
GENE AMPLIFICATION
HALIDES
HALOGEN COMPOUNDS
IONS
MATERIALS
MEMBRANE PROTEINS
METALS
NICKEL COMPOUNDS
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANS
OXIDASES
OXIDOREDUCTASES
PHAGOCYTES
PROTEINS
RNA
SOMATIC CELLS
TRANSITION ELEMENT COMPOUNDS
TRANSITION ELEMENTS