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    Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.

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    Authors
    Martínez-Martínez, Sara
    Gómez del Arco, Pablo
    Armesilla, Angel Luis
    Aramburu, Jose
    Luo, Chun
    Rao, Anjana
    Redondo, Juan Miguel
    Issue Date
    1997
    
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    Abstract
    Dithiocarbamates (DTCs) have recently been reported as powerful inhibitors of NF-kappaB activation in a number of cell types. Given the role of this transcription factor in the regulation of gene expression in the inflammatory response, NF-kappaB inhibitors have been suggested as potential therapeutic drugs for inflammatory diseases. We show here that DTCs inhibited both interleukin 2 (IL-2) synthesis and membrane expression of antigens which are induced during T-cell activation. This inhibition, which occurred with a parallel activation of c-Jun transactivating functions and expression, was reflected by transfection experiments at the IL-2 promoter level, and involved not only the inhibition of NF-kappaB-driven reporter activation but also that of nuclear factor of activated T cells (NFAT). Accordingly, electrophoretic mobility shift assays (EMSAs) indicated that pyrrolidine DTC (PDTC) prevented NF-kappaB, and NFAT DNA-binding activity in T cells stimulated with either phorbol myristate acetate plus ionophore or antibodies against the CD3-T-cell receptor complex and simultaneously activated the binding of AP-1. Furthermore, PDTC differentially targeted both NFATp and NFATc family members, inhibiting the transactivation functions of NFATp and mRNA induction of NFATc. Strikingly, Western blotting and immunocytochemical experiments indicated that PDTC promoted a transient and rapid shuttling of NFATp and NFATc, leading to their accelerated export from the nucleus of activated T cells. We propose that the activation of an NFAT kinase by PDTC could be responsible for the rapid shuttling of the NFAT, therefore transiently converting the sustained transactivation of this transcription factor that occurs during lymphocyte activation, and show that c-Jun NH2-terminal kinase (JNK) can act by directly phosphorylating NFATp. In addition, the combined inhibitory effects on NFAT and NF-KB support a potential use of DTCs as immunosuppressants.
    Citation
    Molecular and Cellular Biology, 17(11): 6437-6447
    Publisher
    American Society for Microbiology
    URI
    http://hdl.handle.net/2436/7738
    DOI
    10.1128/MCB.17.11.6437
    PubMed ID
    9343406
    Additional Links
    https://mcb.asm.org/content/17/11/6437
    Type
    Journal article
    Language
    en
    ISSN
    0270-7306
    ae974a485f413a2113503eed53cd6c53
    10.1128/MCB.17.11.6437
    Scopus Count
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    Research Institute in Healthcare Science

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