Cyclosporin-a sensitive induction of NF-AT in murine B cells

Venkataraman, Lakshmi; Francis, Delicia A.; Wang, Zihua; Liu, Jialing; Rothstein, Thomas L.; Sen, Ranjan

doi:10.1016/1074-7613(94)90097-3

Cited by 115 publications

(86 citation statements)

References 33 publications

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“…Resting cells express only NFAT-1, whereas expression of NFAT-2 is induced to significant levels upon stimulation by Ca 2ϩ -dependent signaling (24,42). In addition, in normal lymphocytes, NFAT-3 is not expressed, and NFAT-4 is only detectable at low levels (29).…”

Section: Discussionmentioning

confidence: 99%

“…Although all members exhibit similar DNA binding specificity, they differ in their tissue distribution and inducibility upon cell stimulation, suggesting that each protein may serve specific functions. Whereas NFAT-1 is constitutively expressed in lymphocytes and in several non-lymphoid cells, NFAT-2 expression has been reported to be induced in activated T and B cells (24,42). To analyze specificity and investigate which NFAT member contributes to the ATP-induced DNA complex, we performed competition and supershift analyses.…”

Section: Cyclosporin a And Fk506 Inhibit P2z Receptor-mediated Nfat Amentioning

confidence: 99%

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P2X7/P2Z Purinoreceptor-mediated Activation of Transcription Factor NFAT in Microglial Cells

Ferrari¹,

Stroh

Schulze‐Osthoff

1999

Journal of Biological Chemistry

146

121

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ATP is released from neurons and other cell types during several physiological and stress conditions under which it exerts various biological effects upon binding to purinoreceptors. A rather peculiar purinoreceptor called P2X 7 /P2Z is expressed on microglial and other myeloic cells. Although increasing evidence implicates an important role for P2Z in inflammatory processes, little information exists about underlying signaling pathways. Here, we report that in N9 microglial cells, extracellular ATP potently activates nuclear factor of activated T cells (NFAT), a central transcription factor involved in cytokine gene expression. ATP activated NFAT rapidly (within 1 min), whereas activation of nuclear factor B was much delayed, with strikingly distinct kinetics. During ATP stimulation, both NFAT-1 and NFAT-2 were activated by a calcineurin-dependent pathway that required the influx of extracellular calcium ions. Based on the pharmacological profile, NFAT activation was specifically mediated by P2Z and not by other purinoreceptors. N9 cells that lacked P2Z but still expressed P2Y purinoreceptors failed to respond to NFAT activation. We conclude that P2Z-mediated NFAT activation may represent a novel mechanism by which extracellular ATP can modulate early inflammatory gene expression within the nervous and immune system.Large amounts of ATP and other nucleotides can be rapidly released from different cellular sources such as nerve terminals, antigen-stimulated T cells, activated platelets, endothelial cells, and other cell types under either physiological and pathological conditions such as hypoxia, stress, and tissue damage. Particularly in the immune and nervous system, extracellular ATP serves as a mediator of cell-to-cell communication by triggering a variety of biological responses including excitatory transmitter function, mitogenic stimulation, or induction of cell death (reviewed in Refs. 1-3). These effects are not the result of nonspecific membrane alterations but rather are mediated through the activation of specific surface molecules called P2 purinoreceptors (reviewed in Refs. 1, 4, and 5). At least two mechanistically distinct subclasses of P2 purinoreceptors are currently known. The metabotrophic P2Y receptors (formerly P2u, P2t, and P2y), which bind either UTP or ATP, initiate their biological effects through the G-proteincoupled activation of phospholipase C and subsequent Ca 2ϩ mobilization from intracellular stores. The P2X receptors are a distinct subfamily of receptors that are related to glutamate receptors and function as ligand-gated ion channels. Engagement of P2X receptors by ATP causes an increase in Ca 2ϩ permeability that is entirely dependent upon extracellular Ca 2ϩ ions. Recently, among the P2X subfamily, the molecular structure of the P2Z receptor, also called P2X 7 , has been elucidated (6, 7). The P2Z receptor contains two transmembrane domains and a large extracellular loop, structural features that are characteristic of members of the P2X family. Unlike other P2X receptors, the ...

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Section: Discussionmentioning

confidence: 99%

Section: Cyclosporin a And Fk506 Inhibit P2z Receptor-mediated Nfat Amentioning

confidence: 99%

P2X7/P2Z Purinoreceptor-mediated Activation of Transcription Factor NFAT in Microglial Cells

Ferrari¹,

Stroh

Schulze‐Osthoff

1999

Journal of Biological Chemistry

146

121

View full text Add to dashboard Cite

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“…Recent studies have shown that NF-AT expression is not restricted to T cells and is probably a feature of all activated lymphoid cells (15)(16)(17). NF-AT consists of two components, a pre-existing cytoplasmic subunit, NF-AT, and a nuclear component consisting of an AP-1 complex (18,19).…”

mentioning

confidence: 99%

The CD40L Promoter Contains Nuclear Factor of Activated T Cells-binding Motifs Which Require AP-1 Binding for Activation of Transcription

Tsytsykova

Tsitsikov

Geha

1996

Journal of Biological Chemistry

116

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Four nuclear factor of activated T cells (NF-AT) binding motifs were found in the murine CD40 ligand promoter. Electrophoretic mobility shift assays using 18-base pair (bp) long oligonucleotides corresponding to the proximal site and nuclear extracts from activated T cells revealed two complexes which were inhibited by cyclosporin A and contained NF-ATc and NF-ATp. Neither complex contained AP-1 proteins. Multimers of the 18-bp oligonucleotides were not active in transient transfection assays using luciferase reporter gene constructs. In contrast, a 30-bp long oligonucleotide bound AP-1 proteins in addition to NF-AT proteins and its multimers strongly induced luciferase gene expression. These results suggested that NF-AT proteins play an important role in the expression of the CD40L gene and that their transcriptional activity requires AP-1 binding.

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“…In turn, the transcription factor NF-AT, normally dephosphorylated by calcineurin, fails to initiate transcription of IL-2 (4, 6). Although most investigations have explored CsA's effect on T cells, CsA was also shown to inhibit B cell proliferation (9,11), to reduce Ab production initiated in vitro or in vivo (8,10,38,39), and to block NF-B activation (12,13). The present study provides strong in vivo evidence that CsA, when combined with a specific blood transfusion, induces tolerance in those B cells that normally elicit a thymusdependent Ab response.…”

Section: Discussionmentioning

confidence: 47%

Specific B Cell Tolerance Is Induced by Cyclosporin A Plus Donor-Specific Blood Transfusion Pretreatment: Prolonged Survival of MHC Class I Disparate Cardiac Allografts

Chun-ping¹,

Shittu²,

Bell³

2000

The Journal of Immunology

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Donor-specific blood transfusion (DST), designed to prolong allograft survival, sensitized recipients of the high-responder PVG-RT1u strain, resulting in accelerated rejection of MHC-class I mismatched (PVG-R8) allografts. Rejection was found to be mediated by anti-MHC class I (Aa) alloantibody. By pretreating recipients 4 wk before grafting with cyclosporin A (CsA) daily (×7), combined with once weekly (×4) DST, rejection was prevented. The investigation explores the mechanism for this induced unresponsiveness. CD4 T cells purified from the thoracic duct of CsA/DST-pretreated RT1u rats induced rejection when transferred to R8 heart-grafted RT1u athymic nude recipients, indicating that CD4 T cells were not tolerized by the pretreatment. To determine whether B cells were affected, nude recipients were pretreated, in the absence of T cells, with CsA/DST (or CsA/third party blood) 4 wk before grafting. The subsequent transfer of normal CD4 T cells induced acute rejection of R8 cardiac allografts in third party- but not DST-pretreated recipients; prolonged allograft survival was reversed by the cotransfer of B cells with the CD4 T cells. Graft survival correlated with reduced production of anti-MHC class I (Aa) cytotoxic alloantibody. The results indicated that the combined pretransplant treatment of CsA and DST induced tolerance in allospecific B cells independently of T cells. The resulting suppression of allospecific cytotoxic Ab correlated with the survival of MHC class I mismatched allografts. The induction of B cell tolerance by CsA has important implications for clinical transplantation.

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Cyclosporin-a sensitive induction of NF-AT in murine B cells

Cited by 115 publications

References 33 publications

P2X7/P2Z Purinoreceptor-mediated Activation of Transcription Factor NFAT in Microglial Cells

P2X7/P2Z Purinoreceptor-mediated Activation of Transcription Factor NFAT in Microglial Cells

The CD40L Promoter Contains Nuclear Factor of Activated T Cells-binding Motifs Which Require AP-1 Binding for Activation of Transcription

Specific B Cell Tolerance Is Induced by Cyclosporin A Plus Donor-Specific Blood Transfusion Pretreatment: Prolonged Survival of MHC Class I Disparate Cardiac Allografts

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