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Opposing roles for RelB and Bcl-3 in regulation of T-box expressed in T cells, GATA-3, and Th effector differentiation.
Corn RA, Hunter C, Liou HC, Siebenlist U, Boothby MR
(2005) J Immunol 175: 2102-10
MeSH Terms: Animals, B-Cell Lymphoma 3 Protein, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, GATA3 Transcription Factor, Humans, Interferon-gamma, Jurkat Cells, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Polycomb Repressive Complex 1, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-rel, T-Box Domain Proteins, T-Lymphocytes, Helper-Inducer, Th1 Cells, Th2 Cells, Transcription Factors
Show Abstract · Added December 10, 2013
CD4+ T cells with a block in the NF-kappaB signaling pathway exhibit decreases in Th1 responses and diminished nuclear levels of multiple transactivating NF-kappaB/Rel/IkappaB proteins. To determine the lineage-intrinsic contributions of these transactivators to Th differentiation, T cells from mice deficient in specific subunits were cultured in exogenous cytokines promoting either Th1 or Th2 differentiation. RelB-deficient cells exhibited dramatic defects in Th1 differentiation and IFN-gamma production, whereas no consistent defect in either Th1 or Th2 responses was observed with c-Rel-deficient cells. In sharp contrast, Bcl-3-null T cells displayed no defect in IFN-gamma production, but their Th2 differentiation and IL-4, IL-5, and IL-13 production were significantly impaired. The absence of RelB led to a dramatic decrease in the expression of T-box expressed in T cells and Stat4. In contrast, Bcl-3-deficient cells exhibited decreased GATA-3, consistent with evidence that Bcl-3 can transactivate a gata3 promoter. These data indicate that Bcl-3 and RelB exert distinct and opposing effects on the expression of subset-determining transcription factors, suggesting that the characteristics of Th cell responses may be regulated by titrating the stoichiometry of transactivating NF-kappaB/Rel/IkappaB complexes in the nuclei of developing helper effector cells.
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21 MeSH Terms
Molecular profiling of the role of the NF-kappaB family of transcription factors during alloimmunity.
Finn PW, He H, Ma C, Mueller T, Stone JR, Liou HC, Boothby MR, Perkins DL
(2002) J Leukoc Biol 72: 1054-62
MeSH Terms: Algorithms, Animals, Cytokines, Gene Expression Profiling, Graft Rejection, Graft Survival, Heart Transplantation, I-kappa B Proteins, Kinetics, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, NF-kappa B, NF-kappa B p50 Subunit, Proto-Oncogene Proteins c-rel, RNA, Messenger, Transplantation, Transplantation Immunology
Show Abstract · Added December 10, 2013
Allograft rejection involves a complex network of multiple immune regulators and effector mechanisms. In the current study, we focused on the role of nuclear factor (NF)-kappaB/Rel. Previous studies had established that deficiency of the p50 NF-kappaB family member prolonged allograft survival only modestly. However, because of its crucial role in signal transduction in inflammatory and immune responses, we hypothesized that other NF-kappaB/Rel family members may produce more profound effects on alloimmunity. Therefore, in addition to p50, we analyzed the role of c-Rel, which is expressed predominantly in lymphocytes. Also, to investigate NF-kappaB activation in T cells, we examined transgenic mice that express a transdominant inhibitor of NF-kappaB [IkappaB(DeltaN)] regulated by a T cell-restricted promoter. Allograft survival was prolonged indefinitely in the c-Rel-deficient and IkappaB(DeltaN)-transgenic recipients. To determine the molecular basis of NF-kappaB modulation of rejection, we analyzed a panel of 58 parameters including effector molecules, chemokines, cytokines, receptors, and cellular markers using hierarchical clustering algorithms and self-organizing maps in p50(-/-), c-Rel(-/-), and IkappaB(DeltaN)-transgenic, experimental groups plus allogeneic-, syngeneic-, and lymphocyte-deficient (alymphoid) control groups. Surprisingly, profiles of gene expression in the c-Rel recipients (which have indefinite graft survival) were similar to the p50(-/-) and allogeneic recipients (which rapidly reject grafts). As expected, gene expression in the IkappaB(DeltaN) recipients (which also have indefinite graft survival) was similar to profiles of nonrejecting syngeneic and alymphoid recipients. Importantly, self-organizing maps identified a small subset of genes including several chemokine receptors and cytokines with expression profiles that correlate with graft survival. Thus, our results demonstrate a crucial role for NF-kappaB in acute allograft rejection, identify different molecular mechanisms of rejection by distinct NF-kappaB family members, and identify a small subset of inducible genes whose inhibition is linked to graft acceptance.
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21 MeSH Terms
Inefficient ZAP-70 phosphorylation and decreased thymic selection in vivo result from inhibition of NF-kappaB/Rel.
Mora AL, Stanley S, Armistead W, Chan AC, Boothby M
(2001) J Immunol 167: 5628-35
MeSH Terms: Animals, Cell Survival, Cells, Cultured, Clonal Deletion, DNA-Binding Proteins, Female, I-kappa B Proteins, Mice, Mice, Transgenic, NF-KappaB Inhibitor alpha, NF-kappa B, Phosphorylation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins c-rel, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Thymus Gland, ZAP-70 Protein-Tyrosine Kinase
Show Abstract · Added December 10, 2013
Signaling from the TCR regulates T lymphoid survival, deletion by apoptosis, and selective clonal expansion. One set of signaling pathways activated during thymic selection leads to degradation of a cytosolic retention protein, the inhibitor of kappaB (IkappaB)alpha, followed by nuclear translocation of the NF-kappaB/Rel family of transcription factors. It has been found previously that NF-kappaB proteins mediate a pathway signaling the survival of mature T cells and protection of thymocytes against TNF-induced apoptosis. In contrast, we show in this study that a transgenic inhibitor of NF-kappaB/Rel signaling interferes with the negative selection of immature thymocytes by endogenous MHC ligands in vivo. Positive selection of the H-Y TCR also was diminished. This attenuation of thymic selection efficiency was associated with decreased ZAP-70 phosphorylation and TCR signaling of CD69 induction. These findings demonstrate that the NF-kappaB transcriptional pathway plays an important role in normal processes of clonal deletion and they indicate that the NF-kappaB/IkappaB axis can regulate the efficiency of TCR signaling.
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19 MeSH Terms
NF-kappaB mediates FGF signal regulation of msx-1 expression.
Bushdid PB, Chen CL, Brantley DM, Yull F, Raghow R, Kerr LD, Barnett JV
(2001) Dev Biol 237: 107-15
MeSH Terms: Animals, Binding Sites, Chick Embryo, Extremities, Fibroblast Growth Factors, Gene Expression Regulation, Developmental, Homeodomain Proteins, MSX1 Transcription Factor, NF-kappa B, Proto-Oncogene Proteins c-rel, RNA, Messenger, Transcription Factors, Transcriptional Activation
Show Abstract · Added March 5, 2014
The nuclear factor-kappaB (NF-kappaB) family of transcription factors is involved in proliferation, differentiation, and apoptosis in a stage- and cell-dependent manner. Recent evidence has shown that NF-kappaB activity is necessary for both chicken and mouse limb development. We report here that the NF-kappaB family member c-rel and the homeodomain gene msx-1 have partially overlapping expression patterns in the developing chick limb. In addition, inhibition of NF-kappaB activity resulted in a decrease in msx-1 mRNA expression. Sequence analysis of the msx-1 promoter revealed three potential kappaB-binding sites similar to the interferon-gamma (IFN-gamma) kappaB-binding site. These sites bound to c-Rel, as shown by electrophoretic mobility shift assay (EMSA). Furthermore, inhibition of NF-kappaB activity significantly reduced transactivation of the msx-1 promoter in response to FGF-2/-4, known stimulators of msx-1 expression. These results suggest that NF-kappaB mediates the FGF-2/-4 signal regulation of msx-1 gene expression.
Copyright 2001 Academic Press.
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13 MeSH Terms
NF-kappa B/Rel participation in the lymphokine-dependent proliferation of T lymphoid cells.
Mora A, Youn J, Keegan A, Boothby M
(2001) J Immunol 166: 2218-27
MeSH Terms: Animals, Cells, Cultured, DNA-Binding Proteins, Gene Expression Regulation, I-kappa B Proteins, Interleukin-4, Lymphocyte Activation, Lymphokines, Mice, Mice, Transgenic, Milk Proteins, NF-KappaB Inhibitor alpha, NF-kappa B, Proto-Oncogene Proteins c-rel, Receptors, Interleukin-2, Receptors, Interleukin-4, STAT5 Transcription Factor, Signal Transduction, T-Lymphocytes, Trans-Activators, Transgenes
Show Abstract · Added December 10, 2013
Proliferative responses of lymphoid cells to IL-2 and IL-4 depend on activation of the cells, but the mechanism(s) by which activation enhances cellular competence to respond to cytokines is not fully understood. The NF-kappaB/Rel family represents one signal transduction pathway induced during such activation. We show in this study that inhibition of NF-kappaB through the expression of an IkappaBalpha (inhibitory protein that dissociates from NF-kappaB) mutant refractory to signal-induced degradation (IkappaBalpha(DeltaN)) interfered with the acquisition of competence to proliferate in response to IL-4 as well as IL-2. Thymocytes and T cells from IkappaBalpha(DeltaN) transgenic mice expressed normal levels of IL-2R subunits. However, transgenic cells exhibited a dramatic defect in Stat5A activation treatment with IL-2, and a similar defect was observed for IL-4-induced Stat5. In contrast, T lymphoid cells with inhibition of NF-kappaB showed normal insulin receptor substrate-2 phosphorylation and only a modest decrease in Stat6 activation and insulin receptor substrate-1 phosphorylation after IL-4 stimulation. These results indicate that the NF-kappaB/Rel/IkappaBalpha system can regulate cytokine receptor capacitation through effects on the induction of downstream signaling by the Stat transcription factor family.
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Critical role of C/EBPdelta and C/EBPbeta factors in the stimulation of the cyclooxygenase-2 gene transcription by interleukin-1beta in articular chondrocytes.
Thomas B, Berenbaum F, Humbert L, Bian H, Béréziat G, Crofford L, Olivier JL
(2000) Eur J Biochem 267: 6798-809
MeSH Terms: Animals, Base Sequence, Binding Sites, CCAAT-Enhancer-Binding Protein-beta, CCAAT-Enhancer-Binding Protein-delta, CCAAT-Enhancer-Binding Proteins, Cartilage, Articular, Cell Nucleus, Cells, Cultured, Chloramphenicol O-Acetyltransferase, Chondrocytes, Cyclooxygenase 2, Female, Gene Deletion, Gene Expression Regulation, Humans, Interleukin-1, Isoenzymes, Kinetics, Membrane Proteins, Models, Biological, Molecular Sequence Data, Mutagenesis, Plasmids, Promoter Regions, Genetic, Prostaglandin-Endoperoxide Synthases, Protein Binding, Proto-Oncogene Proteins c-rel, Rabbits, Sequence Homology, Nucleic Acid, Transcription Factors, Transcription, Genetic
Show Abstract · Added September 18, 2013
The activity of the [-831; +103] promoter of the human cyclooxygenase-2 gene in cultured rabbit chondrocytes is stimulated 2.9 +/- 0.3-fold by interleukin-1beta and this stimulation depends on [-132; -124] C/EBP binding-and [-223; -214] NF-kappaB binding-sites. The C/EBPbeta and C/EBPdelta factors bind to the [-132; -124] sequence. The [-61; -53] sequence is also recognized by C/EBPbeta and C/EBPdelta as well as USF. Mutation of the whole [-61; -53] sequence abolished the stimulation of transcription but single mutations of the C/EBP or USF site did not alter the activity of the promoter, suggesting that the factors bound to the proximal [-61; -53] sequence interact with different members of the general transcription machinery. The [-223; -214] site binds only the p50/p50 homodimer and a non-rel-related protein, but not the transcriptionally active heterodimer p50/p65. The p50/p50 homodimer could interact with the C/EBP family members bound to the [-132; -124] sequence for full stimulation of the COX-2 transcription by interleukin-1beta in chondrocytes. By contrast, the [-448; -449] sequence binds with a low affinity both the p50/p50 homodimeric and p50/p65 heterodimeric forms of NF-kappaB but has no role in the regulation of the human COX-2 promoter in chondrocytes.
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32 MeSH Terms
Preferential role for NF-kappa B/Rel signaling in the type 1 but not type 2 T cell-dependent immune response in vivo.
Aronica MA, Mora AL, Mitchell DB, Finn PW, Johnson JE, Sheller JR, Boothby MR
(1999) J Immunol 163: 5116-24
MeSH Terms: Animals, Bronchial Hyperreactivity, Cell Movement, Cytokines, DNA-Binding Proteins, Eosinophilia, Hypersensitivity, Delayed, I-kappa B Proteins, Immunoglobulin Isotypes, Lung, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, NF-KappaB Inhibitor alpha, NF-kappa B, Proto-Oncogene Proteins c-rel, Respiratory Hypersensitivity, Th1 Cells, Th2 Cells, Transcription Factor RelA
Show Abstract · Added December 10, 2013
T cell function is a critical determinant of immune responses as well as susceptibility to allergic diseases. Activated T cells can differentiate into effectors whose cytokine profile is limited to type 1 (IFN-gamma-dominant) or type 2 (IL-4-, IL-5-dominant) patterns. To investigate mechanisms that connect extracellular stimuli with the regulation of effector T cell function, we have measured immune responses of transgenic mice whose NF-kappa B/Rel signaling pathway is inhibited in T cells. Surprisingly, these mice developed type 2 T cell-dependent responses (IgE and eosinophil recruitment) in a model of allergic pulmonary inflammation. In contrast, type 1 T cell responses were severely impaired, as evidenced by markedly diminished delayed-type hypersensitivity responses, IFN-gamma production, and Ag-specific IgG2a levels. Taken together, these data indicate that inhibition of NF-kappa B can lead to preferential impairment of type 1 as compared with type 2 T cell-dependent responses.
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22 MeSH Terms
Fibroblast growth factor-1 (FGF-1) enhances IL-2 production and nuclear translocation of NF-kappaB in FGF receptor-bearing Jurkat T cells.
Byrd VM, Ballard DW, Miller GG, Thomas JW
(1999) J Immunol 162: 5853-9
MeSH Terms: Biological Transport, CD28 Antigens, Cell Nucleus, DNA-Binding Proteins, Drug Interactions, Fibroblast Growth Factor 1, Fibroblast Growth Factor 2, Humans, I-kappa B Proteins, Jurkat Cells, NF-KappaB Inhibitor alpha, NF-kappa B, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-rel, Receptor Protein-Tyrosine Kinases, Receptor, Fibroblast Growth Factor, Type 1, Receptors, Fibroblast Growth Factor, Response Elements, Signal Transduction, T-Lymphocytes, Transcription, Genetic
Show Abstract · Added November 6, 2013
Fibroblast growth factors (FGFs) are heparin-binding proteins crucial to embryogenesis, angiogenesis, and wound healing. FGF-1 is abundantly expressed in the synovium in rheumatoid arthritis and in rejecting allografts, sites of chronic immune-mediated inflammation. The frequency of FGF-1-responsive T cells is increased in the peripheral blood of these disorders, and a high percentage of infiltrating T cells in rheumatoid arthritis synovium express receptors for FGF-1. To understand the action of FGF-1 in T cells, studies were initiated in Jurkat T cells that express the signaling isoform of FGF receptor-1. These experiments show that FGF-1 stimulation of Jurkat T cells provides a second signal that augments TCR-mediated IL-2 production. Analogous to costimulation via CD28, this activity is mediated through activation of Rel/kappaB, a family of transcription factors known to regulate IL-2 and other activation-inducible proteins. FGF-1 alone induces modest nuclear translocation of kappaB-binding proteins, and this translocation is enhanced by the combination of anti-CD3 and FGF-1. This NF-kappaB binding complex is composed of transcriptionally active p65(RelA)/p50 heterodimers and results primarily from the targeted degradation of IkappaB-alpha, an inhibitor that sequesters Rel/kappaB in the cytoplasm. These data are the first to show a connection between FGF-1 signaling and NF-kappaB activation outside of embryonic development. The signaling events that link FGF receptor-1 engagement and NF-kappaB activation in Jurkat are probably distinct from the CD28 costimulation pathway, since FGF-1-induced Rel/kappaB binding proteins do not contain significant levels of c-Rel and are not identical with the CD28 response complex.
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21 MeSH Terms
Costimulation reverses the defect in IL-2 but not effector cytokine production by T cells with impaired IkappaBalpha degradation.
Aune TM, Mora AL, Kim S, Boothby M, Lichtman AH
(1999) J Immunol 162: 5805-12
MeSH Terms: Animals, CD28 Antigens, CD4-Positive T-Lymphocytes, Cytokines, DNA-Binding Proteins, I-kappa B Proteins, Interferon-gamma, Interleukin-2, Interleukin-4, Mice, Mice, Mutant Strains, Mice, Transgenic, Mutation, NF-KappaB Inhibitor alpha, NF-kappa B, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-rel, Receptor Aggregation, Receptors, Antigen, T-Cell, Response Elements, Signal Transduction
Show Abstract · Added December 10, 2013
Although the transcriptional basis for states of unresponsiveness in primary T cells is unclear, tolerant B lymphocytes exhibit inhibition of both c-Jun N-terminal kinase induction and IkappaBalpha (inhibitor of NF-kappaBalpha) degradation, leading to lower levels of both nuclear AP-1 and NF-kappaB. Expression of an IkappaBalpha mutant resistant to signal-induced degradation in transgenic T cells caused markedly deficient effector cytokine (IL-4, IFN-gamma) production after primary TCR stimulation despite a detectable level of nuclear NF-kappaB. A TCR response element from the IFN-gamma promoter, despite lacking detectable NF-kappaB/Rel sites, was also unresponsive to TCR ligation. Nuclear induction of AP-1 proteins in response to T cell activation was diminished in transgenic T cells. Costimulation induced by anti-CD28 mAb increased IL-2 production, but failed to reverse the defects in effector cytokine production. Taken together, these data indicate that impaired NF-kappaB/Rel signaling in T cells interferes with the signal transduction pathways required for efficient induction of effector cytokine production.
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21 MeSH Terms
Inhibition of NF-kappaB activity results in disruption of the apical ectodermal ridge and aberrant limb morphogenesis.
Bushdid PB, Brantley DM, Yull FE, Blaeuer GL, Hoffman LH, Niswander L, Kerr LD
(1998) Nature 392: 615-8
MeSH Terms: Adenoviridae, Animals, Chick Embryo, Culture Techniques, DNA-Binding Proteins, Embryonic Induction, Gene Expression Regulation, Developmental, Genetic Vectors, Hedgehog Proteins, I-kappa B Proteins, Limb Buds, Morphogenesis, NF-KappaB Inhibitor alpha, NF-kappa B, Protein Biosynthesis, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-rel, Retroviridae, Signal Transduction, Trans-Activators
Show Abstract · Added March 5, 2014
In Drosophila, the Dorsal protein establishes the embryonic dorso-ventral axis during development. Here we show that the vertebrate homologue of Dorsal, nuclear factor-kappa B (NF-kappaB), is vital for the formation of the proximo-distal organizer of the developing limb bud, the apical ectodermal ridge (AER). Transcription of the NF-kappaB proto-oncogene c-rel is regulated, in part, during morphogenesis of the limb bud by AER-derived signals such as fibroblast growth factors. Interruption of NF-kappaB activity using viral-mediated delivery of an inhibitor results in a highly dysmorphic AER, reduction in overall limb size, loss of distal elements and reversal in the direction of limb outgrowth. Furthermore, inhibition of NF-kappaB activity in limb mesenchyme leads to a reduction in expression of Sonic hedgehog and Twist but derepresses expression of the bone morphogenetic protein-4 gene. These results are the first evidence that vertebrate NF-kappaB proteins act to transmit growth factor signals between the ectoderm and the underlying mesenchyme during embryonic limb formation.
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20 MeSH Terms