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

作者：Saito Rumiko; Hirakawa Satoshi; Ohara Hiroshi; Yasuda Makoto; Yamazaki Tomomi; Nishii Shigeaki; Aiba Setsuya^*

来源：Toxicology and Applied Pharmacology, 2011, 254(3): 245-255.

DOI：10.1016/j.taap.2011.04.017

• nickel
• NFAT
• AP-1
• NF-kappa B
• CRAC

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 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-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 NiCl2-treated T cells. The DNA microarray results were verified using real-time PCR and a BioPlex (TM) suspension protein array. Suppression of IL-2 and gene transcription by NiCl2 was also confirmed using Jurkat T cells transfected with IL-2 or IFN-gamma luciferase reporter genes. To explore the NiCl2-regulated signaling pathway, we examined the binding activity of nuclear proteins to NFAT, AP-1, and NF-kappa B consensus sequences. NiCl2 significantly and dose-dependently suppressed NFAT- and AP-1-binding activity, but augmented NF-kappa B-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-kappa B signaling in T cells. These results shed light on the effects of nickel on the molecular regulation of T cell signaling.

• 出版日期2011-8-1