Induction of NF-AT in normal B lymphocytes by anti-immunoglobulin or CD40 ligand in conjunction with IL-4

Choi, Michael S.K.; Brines, Robert; Holman, Mary; Klaus, G. G. B.

doi:10.1016/1074-7613(94)90096-5

Cited by 118 publications

(78 citation statements)

References 46 publications

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“…RCAN1 can interact directly with calcineurin in the cytosol to inhibit the phosphatase activity of the protein required for the dephosphorylation and nuclear translocation of NFAT (17,19,24). NFAT activation has been implicated in the function of a wide variety of immune cells, including T cells (25), B cells (26), mast cells (27), NK cells (28), and macrophages (29), where it induces various cytokines, including IL-2 (25), IL-3 (30), IL-4 (31), IL-5 (32), IL-6 (33), TNF (34), and GM-CSF (35), among others.…”

mentioning

confidence: 99%

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Junkins

MacNeil

et al. 2013

The Journal of Immunology

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Respiratory tract infection with Pseudomonas aeruginosa is a common cause of hospitalization in immune-compromised individuals. However, the molecular mechanisms involved in the immune response to P. aeruginosa lung infection remain incompletely defined. In this study, we demonstrate that the regulator of calcineurin 1 (RCAN1) is a central negative regulator of inflammation in a mouse model of acute bacterial pneumonia using the opportunistic bacterial pathogen P. aeruginosa. RCAN1-deficient mice display greatly increased mortality following P. aeruginosa lung infection despite enhanced neutrophil recruitment and bacterial clearance. This mortality is associated with higher systemic levels of proinflammatory cytokines in RCAN1-deficient animals. These aberrant inflammatory responses coincide with increased transcriptional activity of proinflammatory RCAN1-target proteins NFAT and NF-κB. In addition, we reveal a novel regulatory role for RCAN1 in the ERK/STAT3 pathway both in vitro and in vivo, suggesting that aberrant STAT3 activity may significantly contribute to delayed resolution of inflammatory responses in our model. Together, these findings demonstrate that RCAN1 is a potent negative regulator of inflammation during respiratory tract infections.

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confidence: 99%

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Junkins

MacNeil

et al. 2013

The Journal of Immunology

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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: 48%

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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Induction of NF-AT in normal B lymphocytes by anti-immunoglobulin or CD40 ligand in conjunction with IL-4

Cited by 118 publications

References 46 publications

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

Regulator of Calcineurin 1 Suppresses Inflammation during Respiratory Tract Infections

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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