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

2.50
Hdl Handle:
http://hdl.handle.net/2436/7738
Title:
Blockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.
Authors:
Martínez-Martínez, Sara; Gómez del Arco, Pablo; Armesilla, Angel Luis; Aramburu, Jose; Luo, Chun; Rao, Anjana; Redondo, Juan Miguel
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
Issue Date:
1997
URI:
http://hdl.handle.net/2436/7738
PubMed ID:
9343406
Additional Links:
http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=232496&blobtype=pdf; http://direct.bl.uk/bld/PlaceOrder.do?UIN=034301189&ETOC=RN&from=searchengine; http://mcb.asm.org/cgi/content/abstract/17/11/6437
Type:
Article
Language:
en
ISSN:
0270-7306
Appears in Collections:
Molecular Pharmacology Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorMartínez-Martínez, Sara-
dc.contributor.authorGómez del Arco, Pablo-
dc.contributor.authorArmesilla, Angel Luis-
dc.contributor.authorAramburu, Jose-
dc.contributor.authorLuo, Chun-
dc.contributor.authorRao, Anjana-
dc.contributor.authorRedondo, Juan Miguel-
dc.date.accessioned2007-01-24T13:45:59Z-
dc.date.available2007-01-24T13:45:59Z-
dc.date.issued1997-
dc.identifier.citationMolecular and Cellular Biology, 17(11): 6437-6447en
dc.identifier.issn0270-7306-
dc.identifier.pmid9343406-
dc.identifier.urihttp://hdl.handle.net/2436/7738-
dc.description.abstractDithiocarbamates (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.en
dc.format.extent2339400 bytes-
dc.format.mimetypeapplication/pdf-
dc.language.isoenen
dc.publisherAmerican Society for Microbiologyen
dc.relation.urlhttp://www.pubmedcentral.nih.gov/picrender.fcgi?artid=232496&blobtype=pdfen
dc.relation.urlhttp://direct.bl.uk/bld/PlaceOrder.do?UIN=034301189&ETOC=RN&from=searchengine-
dc.relation.urlhttp://mcb.asm.org/cgi/content/abstract/17/11/6437-
dc.subjectDithiocarbamatesen
dc.subjectTranscription factoren
dc.subjectDTCsen
dc.subjectT-cell activationen
dc.titleBlockade of T-cell activation by dithiocarbamates involves novel mechanisms of inhibition of nuclear factor of activated T cells.en
dc.typeArticleen
dc.format.digYES-

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