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Title: Nickel differentially regulates NFAT and NF-{kappa}B 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-{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 demonstratedmore » 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.« less

Authors:
 [1];  [1];  [2];  [3]; ; ;  [4];  [1]
  1. Department of Dermatology, Tohoku University Graduate School of Medicine, Sendai 980-8574 (Japan)
  2. (Japan)
  3. Department of Clinical Pharmacy, Tohoku University Graduate School of Pharmaceutical Sciences, Sendai 980-8574 (Japan)
  4. Tsuruga Institute of Biotechnology, TOYOBO Co., Ltd., Tsuruga 914-0047 (Japan)
Publication Date:
OSTI Identifier:
21587799
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 254; Journal 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)
Country of Publication:
United States
Language:
English
Subject:
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

Citation Formats

Saito, Rumiko, Hirakawa, Satoshi, Dermatological R and D Skin Research Department, POLA Chemical Industries, Inc., Yokohama 244-0812, Ohara, Hiroshi, Yasuda, Makoto, Yamazaki, Tomomi, Nishii, Shigeaki, and Aiba, Setsuya, E-mail: saiba@med.tohoku.ac.jp. Nickel differentially regulates NFAT and NF-{kappa}B activation in T cell signaling. United States: N. p., 2011. Web. doi:10.1016/j.taap.2011.04.017.
Saito, Rumiko, Hirakawa, Satoshi, Dermatological R and D Skin Research Department, POLA Chemical Industries, Inc., Yokohama 244-0812, Ohara, Hiroshi, Yasuda, Makoto, Yamazaki, Tomomi, Nishii, Shigeaki, & Aiba, Setsuya, E-mail: saiba@med.tohoku.ac.jp. Nickel differentially regulates NFAT and NF-{kappa}B activation in T cell signaling. United States. doi:10.1016/j.taap.2011.04.017.
Saito, Rumiko, Hirakawa, Satoshi, Dermatological R and D Skin Research Department, POLA Chemical Industries, Inc., Yokohama 244-0812, Ohara, Hiroshi, Yasuda, Makoto, Yamazaki, Tomomi, Nishii, Shigeaki, and Aiba, Setsuya, E-mail: saiba@med.tohoku.ac.jp. 2011. "Nickel differentially regulates NFAT and NF-{kappa}B activation in T cell signaling". United States. doi:10.1016/j.taap.2011.04.017.
@article{osti_21587799,
title = {Nickel differentially regulates NFAT and NF-{kappa}B activation in T cell signaling},
author = {Saito, Rumiko and Hirakawa, Satoshi and Dermatological R and D Skin Research Department, POLA Chemical Industries, Inc., Yokohama 244-0812 and Ohara, Hiroshi and Yasuda, Makoto and Yamazaki, Tomomi and Nishii, Shigeaki and Aiba, Setsuya, E-mail: saiba@med.tohoku.ac.jp},
abstractNote = {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.},
doi = {10.1016/j.taap.2011.04.017},
journal = {Toxicology and Applied Pharmacology},
number = 3,
volume = 254,
place = {United States},
year = 2011,
month = 8
}
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