Association of IKBA gene polymorphisms with the development of asthma (original) (raw)

NF-κB subunit-specific regulation of the IκBα promoter

Journal of Biological Chemistry

Stimulation of endothelial cells by cytokines and bacterial lipopolysaccharide leads to activation of the transcription factor NF-KB. NF-KB in turn regulates the expression of several genes involved in the inflammatory reaction, including cell adhesion molecules, interleukins, and transcription factors. One of these induced genes encodes an inhibitor of NF-KB, E C I-~/ I K B~, that contains in its 5' regulatory region six consensus binding sites for NF-KB. W e demonstrate here that these sites display striking differences in their ability in vitro to bind to various NF-KB subunits. In vivo, all six sites contribute, though to varying degrees, to transcription from the ECI-G/IKBa promoter, as demonstrated by deletion and mutation analysis. Among the NF-KB subunits tested p65, the p65/p50 heterodimer and, to a lesser extent, c-Rel, are able to activate transcription, whereas p50 or p50/RelB were inactive. Since many genes regulated by NF-KB contain only one or two DNA-binding sites for this transcription factor, the presence of six functional NF-KB-binding sites in the ECI-6/IKBa promoter represents a unique feature of this gene. * This is publication 607 from our laboratories. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "aduertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. to the GenBankTMIEMBL Data Bank with accession number(s) 230209.

Control of lymphocyte development by nuclear factor-?B

Nat Rev Immunol, 2005

The transcription factor nuclear factor-κB (NF-κB) is essential for both innate and adaptive immunity. It is crucial for the initial responses of sentinel cells to pathogens, as well as for the subsequent events that lead to T-and B-cell-mediated antigen-specific defence. The role of NF-κB in acute innate immune responses is evolutionarily conserved at least as far back as insects, in which NF-κB is responsible for the induction of nearly all responses to pathogens. Recently, NF-κB has also been recognized to be crucial for the development of several mammalian haematopoietic cell lineages and for the formation of secondary lymphoid-organ structures. In this article, we focus on the cell-autonomous roles of NF-κB in developing T and B cells, in which the main, but not exclusive, function of NF-κB is to ensure survival. The precise nature of NF-κB activity, as well as how it is activated and which genes it regulates, is context dependent, varying with the developmental stage and the initiating signal.

Reductions in I B and Changes in NF- B Activity during B Lymphocyte Differentiation

The Journal of Immunology, 2005

The levels and stability of IB⑀ have been examined in unstimulated and stimulated splenic B cells and compared with that of IB␣ and IB␤. Primary murine splenic B cells but not T cells were found to contain high levels of IB⑀ protein, equivalent to levels of the abundant IB␣. Most agents that activate IB␣ and IB␤ degradation do not induce rapid degradation of IB⑀. Interestingly, however, the levels of IB⑀, but not of IB␣ or IB␤, are dramatically reduced upon the stimulation of B cells both in vivo and in vitro. Since IB⑀ exhibits substrate specificity for NF-B Rel homodimers, this suggested the possibility that changes in NF-B-responsive genes might also occur during this transition. Consistent with this hypothesis, we found that a NF-B reporter construct sensitive to p65/RelA homodimers is activated at the time that IB⑀ levels decline following B cell stimulation. In IgG ؉ B cell lines, which contain low levels of IB⑀, this same reporter construct was inactive, suggesting that the increases in Rel homodimer activity that accompany B cell stimulation are transient. However, there are differences in the level of expression of NF-B-responsive genes in these IgG ؉ B cell lines compared with their IgM ؉ counterparts. From these data, we conclude that there are transient changes in NF-B activity due to reductions in IB⑀, which might contribute to long-term, persistent changes that accompany B cell differentiation. We propose an important role for IB⑀ in the differential regulation of nuclear NF-B activity in stimulated B cells.

A novel enhancer in the immunoglobulin lambda locus is duplicated and functionally independent of NF kappa B

Genes & Development, 1990

As a first step toward defining the elements necessary for g immunoglobulin gene regulation, DNase I hypersensitive sites were mapped in the mouse X locus. A hypersensitive site found 15.5 kb downstream of CX4 was present in all the B-cell but not in the T-cell lines tested. This site coincided with a strong B-cell-specific transcriptional enhancer (E~24). This novel enhancer is active in myeloma cells, regardless of the status of endogenous X genes, but is inactive in a T-cell line and in fibroblasts. The enhancer E~a4 functions in the absence of the transcription factor NFKB, which is necessary for K enhancer function. No evidence could be found for NFgB binding by this element. Rearrangement of VX2 to ]CX3 or JCX genes deletes E~24; however, a second strong enhancer was found 35 kb downstream of CXl, which cannot be eliminated by X gene rearrangements. The second X enhancer (E~3.~) is 90% homologous to the E~a4 sequence in the region determined to comprise the active enhancer and likewise lacks the consensus binding site for NFgB. The data support a model for the independent activation of K and X gene expression based on locus-specific regulation at the enhancer level.

Bronchial Asthma, Chronic Obstructive Pulmonary Disease and NF-κB

Current Medicinal Chemistry, 2009

Respiratory diseases place a considerable burden on global health. Bronchial asthma describes many heterogeneous clinical phenotypes that result in chronic bronchial inflammation. Chronic obstructive pulmonary disease (COPD) is one of the most common adult respiratory disorders characterized by chronic airflow limitation that is not fully reversible and is associated with an abnormal inflammatory response of the lungs to noxious particles and gases. Recognition of the global importance and rising prevalence of these diseases and the absence of effective treatments has led to concerted efforts to improve the efficacy of the existing drugs and develop new ones that target cellular and molecular mechanisms that underlie disease pathogenesis. The transcription factor nuclear factor kappa B (NF-B) regulates the expression of a wide array of genes that are involved in the molecular pathobiology of the lung by regulating cellular immune responses, cell adhesion, differentiation, proliferation, angiogenesis and apoptosis.

Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells

The EMBO Journal, 1996

Apoptosis of the WEHI 231 immature B cell lymphoma line following membrane interaction with an antibody against the surface IgM chains (anti-IgM) is preceded by dramatic changes in Nuclear Factor-icB (NF-iB)/ Rel binding activities. An early transient increase in NF-icB/Rel binding is followed by a significant decrease in intensity below basal levels. Here we have explored the role of these changes in Rel-related factors in B cell apoptosis. Treatment of WEH1 231 cells with N-tosyl-L-phenylalanine chloromethyl ketone (TPCK), a protease inhibitor which prevents degradation of the inhibitor of NF-kB (IicB)-a, or with low doses of pyrrolidinedithiocarbamate (PDTC) selectively inhibited NF-iB/Rel factor binding and induced apoptosis. BCI-XL expression protected WEHI 231 cells from apoptosis induced by these agents. Microinjection of WEHI 231 cells with either IcB-a-GST protein or a c-Rel affinity-purified antibody induced apoptosis. Ectopic c-Rel expression ablated apoptosis induced by TPCK or anti-IgM. Treatment of BALENLM 17 and A20 B lymphoma cells or normal murine splenic B lymphocytes with either TPCK or PDTC also resulted in apoptosis. These findings indicate that the drop in NF-icB/Rel binding following anti-IgM treatment activates apoptosis of WEHI 231 cells; furthermore, they implicate the NF-icB/Rel family in control of apoptosis of normal and transformed B cells.