SEARCH · PubMed Health

Results for “Transcription Factor RelB”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources

PubMed1999

Expression of the RelB transcription factor correlates with the activation of human dendritic cells.

The RelB gene product is a member of the nuclear factor (NF)-kappaB family of transcription factors. It has been identified recently within mouse antigen-presenting cells and human monocyte-derived dendritic cells (DC). Disruption of the mouse RelB gene is accompanied, amongst other phenotypes, by abnormalities in the antigen-presenting cell lineages. In order to define RelB expression during human DC differentiation, we have analysed RelB mRNA by reverse transcriptase-polymerase chain reaction and RelB protein by intracellular staining in CD34+ precursors and different types of DC preparations. RelB mRNA was not detected in CD34+ precursor populations. Fresh blood DC (lineage-human leucocyte antigen-DR+ (lin-HLA-DR+)) lacked RelB mRNA and cytoplasmic RelB protein but a period of in vitro culture induced RelB expression in blood DC. Purified Langerhans' cells (LC) (CD1a+ HLA-DR+) failed to express RelB mRNA. Immunocytochemical staining identified RelB protein in human skin epithelium. RelB protein was expressed in a very few CD1a+, CD83+ or CMRF-44+ dermal DC but was not present in CD1a+ LC. Tonsil DC (lin-HLA-DR+ CMRF-44+) were positive for RelB mRNA and RelB protein. Intestinal DC (HLA-DR+) also lacked immunoreactive RelB protein. The majority of interdigitating CD83+, CMRF-44+, CMRF-56+ or p55+ DC located in paracortical T-lymphocyte areas of lymph node and tonsil contained RelB protein. The expression of RelB mRNA and RelB protein correlates with the activated phase of blood DC and the postmigration cell (activated) stage of tissue DC development.

Antigens, CD34↗

PubMed2000

Mice lacking the transcription factor RelB develop T cell-dependent skin lesions similar to human atopic dermatitis.

Mice with a targeted disruption of the Rel / NF-kappaB family member RelB develop a complex inflammatory phenotype and hematopoietic abnormalities. RelB-deficient (relB(- / -)) mice were clinically normal until 4 - 10 weeks after birth when thickening of the skin and hair loss developed. Histological and immunohistochemical evaluation of relB(- / -) skin lesions revealed hyperkeratosis and marked epidermal hyperplasia. Many CD4(+) T cells and eosinophils mixed with lesser numbers of CD8(+) T cells and neutrophils were present in the dermis. There was a moderate increase of MHC class II-positive dermal dendritic cells and dermal mast cells. Increased expression of Th2 cytokines correlated with increased mRNA levels of eotaxin and CCR3 in relB(- / -) skin. The dermatitis did not develop in the offspring of relB(- / -) mice crossed with transgenic mice that lack peripheral T cells, demonstrating that the skin lesions were T cell dependent. The dermatitis observed in RelB-deficient mice had many similarities with atopic dermatitis in human patients including infiltrating CD4(+) T cells and eosinophils in the skin, increased number of eosinophils in the blood and increased serum IgE. Thus, the relB(- / -) mouse should be a useful model to study the pathogenesis of this common allergic human disease.

Animals↗

PubMed2001

The chicken RelB transcription factor has transactivation sequences and a tissue-specific expression pattern that are distinct from mammalian RelB.

Rel/NF-kappaB proteins are eukaryotic transcription factors that control the expression of genes involved in a large variety of cellular processes. Rel proteins share a highly conserved DNA-binding/dimerization domain called the Rel Homology (RH) domain. We have constructed and characterized a composite cDNA encoding most of the chicken RelB transcription factor. The predicted chicken RelB protein has a high degree of sequence similarity to other vertebrate RelB proteins within the RH domain, but is much less conserved outside this domain. Chicken RelB does not bind DNA as a homodimer, but forms DNA-binding heterodimers with NF-kappaB p50 or p52. Overexpressed chicken RelB localizes to the nucleus in chicken embryo fibroblasts, and the nonconserved C-terminal sequences of chicken RelB contain a transactivation domain that functions in chicken and mouse fibroblasts. Thus, chicken RelB has functional properties similar to other vertebrate RelB proteins. However, Western blotting of diverse chicken tissues indicates that chicken RelB is more widely expressed than mammalian RelB.

Active Transport, Cell Nucleus↗

PubMed2006

A role for the transcription factor RelB in IFN-alpha production and in IFN-alpha-stimulated cross-priming.

Chimeric mice generated with bone marrow from RelB-deficient (-/-), RelB-heterozygous (+/-) and wild-type (+/+) mice were used to determine how total or partial absence of the transcription factor RelB in haematopoietic cells affects the immune response generated after lymphocytic choriomeningitis virus (LCMV) infection. In RelB(-/-) chimeras, early virus replication was enhanced and LCMV clearance was impaired. Although plasmacytoid dendritic cell numbers were similar, serum interferon (IFN)-alpha levels in RelB(-/-) and RelB(+/-) chimeras were markedly lower than in RelB(+/+) chimeras during early LCMV infection. Further, both RelB(-/-) and RelB(+/-) chimeras mounted a lower-magnitude LCMV-specific CD8(+) T cell response than their RelB(+/+) counterparts, although the LCMV-specific CD8(+) T cells present were differentiated into functional cytotoxic cells. In LCMV-infected RelB(-/-) mice, induction of cross-priming to an independently injected soluble protein, which depends on the IFN-alpha/beta made during the viral infection, was also impaired. Notably, provision of exogenous IFN-alpha did not restore the ability of RelB(-/-) mice to cross-prime. In summary, these results show that the RelB/NF-kappaB pathway is required for optimal IFN-alpha production after LCMV infection and suggest a crucial role for RelB in IFN-alpha-stimulated cross-priming of CD8(+) T cell responses.

Animals↗

PubMed1996

RelB, a member of the Rel/NF-kappa B family of transcription factors.

RelB, originally identified as an immediate early gene product, is a member of the Rel/NF-kappa B family of transcription factors important for the regulation of genes involved in immune and inflammatory processes. RelB by itself is inactive due to its inability to homodimerize and to bind to kappa B sequences. However, in the presence of the Rel/NF-kappa B proteins p50 or p52, RelB is a potent transactivator. Transcriptional activation domains were identified in the NH2 and COOH termini of RelB separated by the approximately 300 amino acids spanning the Rel homogy domain (RHD). The last 120 amino acids of this domain are necessary for the dimerization of RelB and were analyzed in detail by in vitro mutagenesis. RelB forms complexes with p50 and p52 but not with RelA and c-Rel. In contrast to RelA-containing complexes, RelB-containing complexes are only weakly inhibited in their activity by I kappa B alpha. Furthermore, in lymphoid tissues RelB is not associated with I kappa B alpha. In contrast to other members of the Rel/NF-kappa B family, high expression of RelB is limited to interdigitating dendritic cells. Mice with a targeted disrupted relB locus show phenotypic abnormalities including multifocal, mixed inflammatory cell infiltration in several organs, myeloid hyperplasia, splenomegaly due to extramedullary hematopoiesis, and a reduced population of thymic dendritic cells.

Animals↗

PubMed2005

Lymphotoxin alpha 1 beta 2: a critical mediator in V alpha 14i NKT cell differentiation.

Lymphotoxin (LT) alpha 1 beta 2, a tumour necrosis factor (TNF) cytokine critically involved in lymphoid organogenesis, is indispensable for the differentiation of V alpha 14i natural killer T (NKT) cells, a lymphocyte subset with important immunoregulatory properties. However, it is not required for the development of conventional T-cells. LT alpha 1 beta 2 signals through the LT beta receptor, which is expressed on non-lymphoid cells. Triggering of this receptor induces a unique signalling cascade leading to the activation of the transcription factor RelB through activation of NF-kappa B inducing kinase. This pathway is required for V alpha 14i NKT cell differentiation as appears from studies in gene-deficient animals. By reciprocal bone marrow chimeras, it was shown that RelB is required in a radiation-resistant host cell or stromal cell for normal V alpha 14i NKT cell development, presumably in the thymic stroma. These stromal cells are not required for the positive selection of these cells but rather play a prominent role in their terminal differentiation. Altogether, these observations underscore the unique developmental requirements of this particular lymphocyte subset.

Animals↗

PubMed2002

Adenovirus type 5 vectors induce dendritic cell differentiation in human CD14(+) monocytes cultured under serum-free conditions.

To determine whether infection by a model virus is capable of initiating dendritic cell (DC) differentiation, human CD14(+) peripheral blood monocytes were infected with replication-defective type 5 adenovirus. Under serum-free conditions, this resulted in differentiation of a majority of cells toward a DC phenotype within 36 to 48 hours, without the need for cytokine-induced predifferentiation. Infection induced DC morphology and altered the expression of surface markers, including loss of CD14, de novo induction of CD83 and CD25, and strongly augmented expression of CD86, CD80, CD40, and HLA-DR and HLA class I molecules. Differentiated cells maintained immunophenotype without loss of viability for at least 2 days after removal of the differentiation agent and cytokines. A greatly enhanced capacity to stimulate T-lymphocyte alloproliferation and increased expression of the DC-associated transcription factor RelB were observed. Virus without transgene was found to induce changes similar to transgene-expressing viruses. RelB up-regulation and DC immunophenotype were sensitive to the antioxidant N-acetylcysteine, suggesting a critical role for nuclear factor kappaB. RNAse protection assays revealed elevated levels of messenger RNA for a number of chemokines and cytokines associated with DCs. Finally, during differentiation, adenovirus-infected monocytes were shown to secrete chemokines and cytokines, including tumor necrosis factor-alpha (TNF-alpha). Furthermore, a TNF-alpha-neutralizing antibody inhibited the expression of some DC surface markers, indicating a contributing role for this cytokine in the adenovirus-induced differentiation of DC from monocytes. These findings have implications for the biology of monocytes as precursors to DCs and also for the use of recombinant adenovirus in vaccines or gene therapy.

Acetylcysteine↗

PubMed2000

Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response.

B lymphocyte stimulator (BLyS) is a newly identified monocyte-specific TNF family cytokine. It has been implicated in the development of autoimmunity, and functions as a potent costimulator with antiimmunoglobulin M in B cell proliferation in vitro. Here we demonstrate that BLyS prominently enhances the humoral responses to both T cell-independent and T cell-dependent antigens, primarily by attenuation of apoptosis as evidenced by the prolonged survival of antigen-activated B cells in vivo and in vitro. BLyS acts on primary splenic B cells autonomously, and directly cooperates with CD40 ligand (CD40L) in B cell activation in vitro by protecting replicating B cells from apoptosis. Moreover, although BLyS alone cannot activate the cell cycle, it is sufficient to prolong the survival of naive resting B cells in vitro. Attenuation of apoptosis by BLyS correlates with changes in the ratios between Bcl-2 family proteins in favor of cell survival, predominantly by reducing the proapoptotic Bak and increasing its prosurvival partners, Bcl-2 and Bcl-xL. In either resting or CD40L-activated B cells, the NF-kappaB transcription factors RelB and p50 are specifically activated, suggesting that they may mediate BLyS signals for B cell survival. Together, these results provide direct evidence for BLyS enhancement of both T cell-independent and T cell-dependent humoral immune responses, and imply a role for BLyS in the conservation of the B cell repertoire. The ability of BLyS to increase B cell survival indiscriminately, at either a resting or activated state, and to cooperate with CD40L, further suggests that attenuation of apoptosis underlies BLyS enhancement of polyclonal autoimmunity as well as the physiologic humoral immune response.

2,4-Dinitrophenol↗

PubMed1998

Phorbol esters induce differentiation of human CD34+ hemopoietic progenitors to dendritic cells: evidence for protein kinase C-mediated signaling.

The intracellular signals that mediate the differentiation of pluripotent hemopoietic progenitors to dendritic cells (DC) are largely undefined. We have found that the phorbol ester PMA by itself induced 47% +/- 8.7% of input human CD34+ hemopoietic progenitors to differentiate into cells with morphology and surface Ag phenotype characteristic of DC by day 7 of culture. Functionally, PMA-generated DC processed and presented whole soluble Ag and also induced resting T cell proliferation and Ag-specific CTL effector function. Unlike cytokine-driven DC differentiation, PMA suppressed proliferation and induced cell death (in part via apoptosis) in cells that did not differentiate to DC. The effects of PMA were blocked by inhibitors of protein kinase C activation, suggesting a central role for this signaling molecule. PMA-mediated signaling also induced expression of the RelB transcription factor, an NF-kappaB family member implicated in DC differentiation. These findings suggest that phorbol esters activate protein kinase C, which then initiates the terminal component of an intracellular signaling pathway(s) involved in the DC differentiation of CD34+ hemopoietic progenitors.

Antigen Presentation↗

PubMed2005

Regulation of RelB expression during the initiation of dendritic cell differentiation.

The transcription factor RelB is required for proper development and function of dendritic cells (DCs), and its expression is upregulated early during differentiation from a variety of progenitors. We explored this mechanism of upregulation in the KG1 cell line model of a DC progenitor and in the differentiation-resistant KG1a subline. RelB expression is relatively higher in untreated KG1a cells but is upregulated only during differentiation of KG1 by an early enhancement of transcriptional elongation, followed by an increase in transcription initiation. Restoration of protein kinase CbetaII (PKCbetaII) expression in KG1a cells allows them to differentiate into DCs. We show that PKCbetaII also downregulated constitutive expression of NF-kappaB in KG1a-transfected cells and restores the upregulation of RelB during differentiation by increased transcriptional initiation and elongation. The two mechanisms are independent and sensitive to PKC signaling levels. Conversely, RelB upregulation was inhibited in primary human monocytes where PKCbetaII expression was knocked down by small interfering RNA targeting. Altogether, the data show that RelB expression during DC differentiation is controlled by PKCbetaII-mediated regulation of transcriptional initiation and elongation.

Cell Differentiation↗

PubMed1997

Dendritic-like cells from relB mutant mice.

Mice deficient in the NF-kappa B transcription factor relB appear to have defects in the production of mature dendritic cells, as secondary lymphoid tissues are absent, and spleen cells show a significant loss of antigen presenting function. Moreover, the thymus appears to be impaired in negative selection, and immune responses in vivo are poor. Since dendritic cell precursors such as skin Langerhans cells appear to be normal, we sought information on the nature of the dendritic cell defect in these mice. Cultures of mutant bone marrow in the presence of GM-CSF revealed a delay in the accumulation of cells with dendritic cell features relative to controls; however, these cells were nearly as potent on a per cell basis as wild type cells in the stimulation of allogeneic mixed lymphocyte cultures. Similarly, skin Langerhans cells from mutant mice also showed significant ability to stimulate allogeneic T cells in culture. Since these findings cannot explain the defect in immune responses and the absence of secondary lymphoid tissues, we also looked at the ability of the relB mutant dendritic-like cells to form aggregates in vitro with naive syngeneic T cells. In this case, while wild type dendritic cells generated compact aggregates with T cells, relB mutant cells only formed irregular small aggregates. Thus, while relB mutant dendritic-like cells have some functions of mature dendritic cells, other functions are deficient. Understanding the role of relB in regulation of these functions should lead to a greater understanding of the molecular basis of dendritic cell development and function.

Animals↗

PubMed2004

RelB regulates human dendritic cell subset development by promoting monocyte intermediates.

In humans, epithelial Langerhans cells (LCs) and monocyte-derived/interstitial dendritic cells (DCs) constitute 2 myeloid DC sublineages. Molecular mechanisms involved in their development from common myeloid progenitors remain poorly defined. Here we demonstrate that the nuclear factor-kappaB (NF-kappaB) transcription factor RelB regulates the generation of monocytic CD14(+)CD11b(+) precursors of interstitial DCs from human hematopoietic progenitors. RelB overexpression promoted, whereas endogenous RelB inhibition (by p100DeltaN) blocked, precursor cell development along this DC subset pathway. RelB inhibition specifically arrested precursor progression from CD14(lo)CD11b(-) to CD14(+)CD11b(+) stages. Precursors were still capable of LC and granulocyte differentiation but were defective in macrophage-colony-stimulating factor (M-CSF)-dependent monocyte/macrophage differentiation. RelB inhibition markedly differed from classical NF-kappaB signaling inhibition because IkappaBalpha superrepressor (IkappaBalpha-SR), but not p100DeltaN, impaired LC/DC differentiation, DC adhesion, and progenitor cell proliferation. Although RelB up-regulation and nuclear translocation are regarded as hallmarks of human myeloid DC maturation, ectopic RelB overexpression failed to promote DC maturation. Our results suggest that RelB regulates human monopoiesis and monocyte-derived DC subset development.

Cell Adhesion↗

PubMed1998

RelB is essential for the development of myeloid-related CD8alpha- dendritic cells but not of lymphoid-related CD8alpha+ dendritic cells.

The transcription factor RelB had been shown to be important for dendritic cell (DC) development, but the type of DC involved was not clear. Here, we report that RelB mRNA is expressed strongly in CD8alpha- DEC-205- DC but only weakly in CD8alpha+ DEC-205+ DC. In addition, CD8alpha+ DEC-205+ DC are present and functional in RelB null mice, the DC deficiency being mainly in the CD8alpha- DEC-205- population. By constructing bone-marrow chimeric mice, we demonstrate that the partial deficiency in RelB null thymic DC is a secondary effect of disrupted thymic architecture. However, the deficiency in splenic CD8alpha- DEC-205- DC is a direct, stem cell intrinsic effect of the RelB mutation. Thus, RelB selectively regulates a myeloid-related DC lineage.

Animals↗

PubMed2003

Direct transcriptional regulation of RelB by 1alpha,25-dihydroxyvitamin D3 and its analogs: physiologic and therapeutic implications for dendritic cell function.

The nuclear factor-kappaB (NF-kappaB) protein RelB plays a unique role in dendritic cell (DC) function and, as such, is an important regulator of antigen presentation and immune regulation. In this study, inhibition of RelB expression in DCs exposed to an analog of the active form of vitamin D3 (1alpha,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3)) was observed and shown to be mediated by the vitamin D receptor (VDR). Potential vitamin D response elements were identified within promoter regions of human and mouse relB genes. In gel shift experiments, these motifs specifically bound VDR.retinoid X receptor-alpha complexes. Reporter assays confirmed that transcriptional activity of human and mouse relB promoters was inhibited by 1alpha,25-(OH)2D3 agonists in a DC-derived cell line. The inhibition was abolished by mutagenesis of the putative vitamin D response elements and was enhanced by overexpression of VDR. Mutagenesis of NF-kappaB response elements within the relB promoter did not affect the magnitude of 1alpha,25-(OH)2D3 analog-mediated inhibition, ruling out an indirect effect on NF-kappaB signaling. Glucocorticoid caused additional inhibition of relB promoter activity when combined with the 1alpha,25-(OH)2D3 analog. This effect was dependent on the integrity of the NF-kappaB response elements, suggesting separate regulatory mechanisms for the two steroid pathways on this promoter. We conclude that relB is a direct target for 1alpha,25-(OH)2D3-mediated negative transcriptional regulation via binding of VDR.retinoid X receptor-alpha to discrete DNA motifs. This mechanism has important implications for the inhibitory effect of 1alpha,25-(OH)2D3 on DC maturation and for the potential immunotherapeutic use of 1alpha,25-(OH)2D3 analogs alone or combined with other agents.

Animals↗

PubMed2000

Differential expression of Rel/NF-kappaB and octamer factors is a hallmark of the generation and maturation of dendritic cells.

A key feature of maturation of dendritic cells is the down-regulation of antigen-processing and up-regulation of immunostimulatory capacities. To study the differential expression of transcription factors in this process, we investigated the nuclear translocation and DNA binding of Rel/NF-kappaB and octamer factors during in vitro generation and maturation of dendritic cells compared with macrophage development. RelB was the only factor strongly up-regulated during the generation of both immature dendritic cells and macrophages. Cytokine-induced maturation of dendritic cells resulted in an increase in nuclear RelB, p50, p52, and especially c-Rel, whereas cytokine-treated macrophages responded poorly. This up-regulation of NF-kappaB factors did not correlate with lower levels of cytosolic NF-kappaB inhibitors, the IkappaBs. One IkappaB, Bcl-3, was strongly expressed only in mature dendritic cells. Furthermore, generation and maturation of dendritic cells led to a continuous down-regulation of the octamer factor Oct-2, whereas monocytes and macrophages displayed high Oct-2 levels. A similar pattern of maturation-induced changes in transcription factor levels was found in cultured murine epidermal Langerhans cells, suggesting a general physiological significance of these findings. Finally, this pattern of differential activation of Rel and octamer factors appears to be suitable in determining the maturation stage of dendritic cells generated by treatment with different cytokine combinations in vitro. (Blood. 2000;95:277-285)

Animals↗

PubMed1996

A role for nuclear NF-kappaB in B-cell-specific demethylation of the Igkappa locus.

The immunoglobulin kappa gene is specifically demethylated during B-cell maturation in a process which utilizes discrete cis-acting modules such as the intronic kappa enhancer element and the matrix attachment region (MAR). While any MAR sequence is sufficient for this reaction, mutation analysis indicates that tissue specificity is mediated by kappaB binding sequences within the kappa intronic enhancer. The plasmacytoma cell line S107 lacks kappaB binding activity and fails to demethylate the kappa locus. However, B-cell specific demethylation is restored by the introduction of an active kappaB binding protein gene relB. This represents the first demonstration of a trans-acting factor involved in cell-type-specific demethylation, and suggests that the same protein-DNA recognition system used for transcription may also contribute to the earlier developmental events that bring about activation of the kappa locus.

B-Lymphocytes↗

PubMed2001

Synthesis of C-X-C and C-C chemokines by human peritoneal fibroblasts: induction by macrophage-derived cytokines.

Leukocyte accumulation during peritonitis is believed to be controlled by chemotactic factors released by resident peritoneal macrophages or mesothelial cells. Recent data indicate, however, that in many tissues fibroblasts play a key role in mediating leukocyte recruitment. We have therefore examined human peritoneal fibroblasts (HPFBs) for the expression and regulation of C-X-C and C-C chemokines. Quiescent HPFBs secreted monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-8 constitutively. This release could be dose-dependently augmented with the pro-inflammatory cytokines IL-1beta and tumor necrosis factor-alpha. Stimulated IL-8 production reached a plateau within 48 hours while MCP-1 continued to accumulate throughout 96 hours. Induction of IL-8 and MCP-1 synthesis by HPFBs was also triggered by peritoneal macrophage-conditioned medium. This effect was partly related to the presence of IL-1beta as demonstrated by IL-1 receptor antagonist inhibition. Pretreatment of HPFBs with actinomycin D or puromycin dose-dependently reduced cytokine-stimulated IL-8 and MCP-1 secretion, which suggested de novo chemokine synthesis. Indeed, exposure of HPFBs to IL-1beta and tumor necrosis factor-alpha produced a significant up-regulation of IL-8 and MCP-1 mRNA. This effect was associated with the rapid induction of nuclear factor-kappaB binding activity mediated through p65 and p50 subunits, and with a transient increase in the mRNA expression for RelB and inhibitory protein kappaB-alpha proteins. These data indicate that peritoneal fibroblasts are capable of generating large quantities of chemokines under a tight control of nuclear factor-kappaB/Rel transcription factors. Thus, peritoneal fibroblast-derived chemokines may contribute to the intraperitoneal recruitment of leukocytes during peritonitis.

Cells, Cultured↗

PubMed1996

Inducible activation of RelB in fibroblasts.

RelB, a member of NF-kappaB/Rel family of transcriptional regulators, is an immediate-early gene product that mediates constitutive lymphoid-specific kappaB-directed gene expression. Data presented here show that RelB also functions as a mitogen-inducible DNA binding activity in fibroblasts. Activation of RelB was observed in three mouse fibroblast lines, and agents activating RelB in quiescent and cycling cells included platelet-derived growth factor, phorbol ester, and serum. Additional data implicate cyclic AMP in the regulation of RelB activity. These findings suggest that RelB may play different roles in different cell types.

3T3 Cells↗