Abstract
To investigate the function of NF-κB RelA (p65), we generated mice deficient in this NF-κB family member by homologous recombination. Mice lacking RelA showed liver degeneration and died around embryonic day 14.5. To elucidate the role of RelA in lymphocyte development and function, we transplanted fetal liver cells of 13.5-day embryos from heterozygote matings into irradiated SCID mice. Within 4 weeks, both T and B cells had developed in the SCID mice receiving relA−/− fetal liver transplants, similar to the relA+/+ and +/− cases. T cells were found to mature to Thy-1+/TCRαβ+/CD3+/CD4+ or CD8+, while B cells had the ability to differentiate to IgM+/B220+ and to secrete immunoglobulins. However, the secretion of IgG1 and IgA was reduced in RelA-deficient B cells. Furthermore, both T and B cells lacking RelA showed marked reduction in proliferative responses to stimulation with Con A, anti-CD3, anti-CD3+anti-CD28, LPS, anti-IgM, and PMA+calcium ionophore. The results indicate that RelA plays a critical role in production of specific Ig isotypes and also in signal transduction pathways for lymphocyte proliferation.
References
44
Referenced
236
10.1146/annurev.immunol.14.1.649
/ Annu Rev Immunol / The NF-κB and IκB proteins: New discoveries and insights by Baldwin (1996)10.1016/0092-8674(86)90346-6
/ Cell / Multiple nuclear factors interact with the immunoglobulin enhancer sequences by Sen (1986)10.1146/annurev.iy.12.040194.001041
/ Annu Rev Immunol / Function and activation of NF-κB in the immune system by Baeuerle (1994){'key': '2023072507143220100_B4', 'first-page': '5349', 'article-title': 'Sequential induction of NF-κB/Rel family protein during B-cell terminal differentiation', 'volume': '14', 'author': 'Liou', 'year': '1994', 'journal-title': 'Mol Cell Biol'}
/ Mol Cell Biol / Sequential induction of NF-κB/Rel family protein during B-cell terminal differentiation by Liou (1994)10.1016/S0021-9258(18)98663-1
/ J Biol Chem / Activation of interleukin-2 gene transcription via T-cell surface molecule CD28 is mediated through an NF-κB-like response element by Verweij (1991)10.1084/jem.170.5.1737
/ J Exp Med / Identification of a functional NF-κB binding site in the murine T cell receptor β2 locus by Jamieson (1989)10.1073/pnas.90.5.1696
/ Proc Natl Acad Sci USA / The interleukin 2 CD28-responsive complex contains at least three members of the NF-κB family: c-Rel, p50, and p65 by Ghosh (1993){'key': '2023072507143220100_B8', 'first-page': '2327', 'article-title': 'Activation of interleukin-6 gene expression through the NF-κB transcription factor', 'volume': '10', 'author': 'Libermann', 'year': '1990', 'journal-title': 'Mol Cell Biol'}
/ Mol Cell Biol / Activation of interleukin-6 gene expression through the NF-κB transcription factor by Libermann (1990){'key': '2023072507143220100_B9', 'first-page': '1498', 'article-title': 'Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four κB-like motifs and of constitutive and inducible forms of NF-κB', 'volume': '10', 'author': 'Collart', 'year': '1990', 'journal-title': 'Mol Cell Biol'}
/ Mol Cell Biol / Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four κB-like motifs and of constitutive and inducible forms of NF-κB by Collart (1990)10.4049/jimmunol.147.2.416
/ J Immunol / Physiologic activation of T cells via the T cell receptor induces NF-κB by Jamieson (1991)10.1038/376167a0
/ Nature (Lond) / Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB by Beg (1995)10.1101/gad.9.16.1965
/ Genes Dev / Mice lacking the c-relproto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-expression by Kontgen (1995)10.1016/0092-8674(95)90416-6
/ Cell / Multiorgan inflammation and hematopoietic abnormalities in mice with a targeted disruption of RelB, a member of the NF-κB/ Rel family by Weih (1995)10.1016/0092-8674(95)90415-8
/ Cell / Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses by Sha (1995)10.1101/gad.9.22.2736
/ Genes Dev / Constitutive NF-κB activation, enhanced granulopoiesis, and neonatal lethality in IκBα-deficient mice by Beg (1995)10.1016/0092-8674(91)90320-X
/ Cell / DNA binding and IκB inhibition of the cloned p65 subunit of NF-κB, a rel-related polypeptide by Nolan (1991)10.1038/292154a0
/ Nature (Lond) / Establishment in culture of pluripotential cells from mouse embryos by Evans (1981)10.1038/336348a0
/ Nature (Lond) / Disruption of the proto-oncogene int-2in mouse embryoderived stem cells: a general strategy for targeting mutations to non-selectable genes by Mansour (1988)10.1093/nar/3.9.2303
/ Nucleic Acids Res / A general method for isolation of high molecular weight DNA from eukaryotes by Blin (1976)10.1021/bi00591a005
/ Biochemistry / Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease by Chirgwin (1979){'key': '2023072507143220100_B21', 'first-page': '5473', 'article-title': 'The mouse c-relprotein has an N-terminal regulatory domain and a C-terminal transcriptional transactivation domain', 'volume': '10', 'author': 'Bull', 'year': '1990', 'journal-title': 'Mol Cell Biol'}
/ Mol Cell Biol / The mouse c-relprotein has an N-terminal regulatory domain and a C-terminal transcriptional transactivation domain by Bull (1990)10.1016/0092-8674(90)90276-K
/ Cell / Cloning of the p50 DNA binding subunit of NF-κB: homology to rel and dorsal. by Ghosh (1990){'key': '2023072507143220100_B23', 'first-page': '674', 'article-title': 'RelB, a new Rel family transcription activator that can interact with p50-NF-κB', 'volume': '12', 'author': 'Ryseck', 'year': '1992', 'journal-title': 'Mol Cell Biol'}
/ Mol Cell Biol / RelB, a new Rel family transcription activator that can interact with p50-NF-κB by Ryseck (1992)10.1038/301527a0
/ Nature (Lond) / A severe combined immunodeficiency mutation in the mouse by Bosma (1983)10.1126/science.7855601
/ Science (Wash DC) / DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect by Kirchgessner (1995)10.4049/jimmunol.142.8.2736
/ J Immunol / Characterization of a monoclonal antibody which detects all murine αβ T cell receptors by Kubo (1989)10.1073/pnas.84.5.1374
/ Proc Natl Acad Sci USA / Identification of a monoclonal antibody specific for a murine T3 polypeptide by Leo (1987)10.4049/jimmunol.131.5.2445
/ J Immunol / Characterization of the murine T cell surface molecule, designated L3T4, identified by monoclonal antibody GK1.5: similarity of L3T4 to the human Leu-3/T4 molecule by Dialynas (1983)10.1111/j.1600-065X.1979.tb00289.x
/ Immunol Rev / Xenogenic monoclonal antibodies to mouse lymphoid differentiation antigen by Ledbetter (1979)10.1073/pnas.80.18.5694
/ Proc Natl Acad Sci USA / Identification and initial characterization of a rat monoclonal antibody reactive with the murine interleukin 2 receptor-ligand complex by Malek (1983)10.1016/S0171-2985(11)80156-7
/ Immunobiol / Prevention of mortality by in vivodepletion of αβ T cells in murine lethal listeriosis and involvement of γδ T cells in bacterial elimination by Matsutake (1995)10.1083/jcb.119.3.493
/ J Cell Biol / Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation by Gavrieli (1992){'key': '2023072507143220100_B33', 'first-page': '41', 'article-title': 'Simultaneous determination of cell surface antigens and apoptosis', 'volume': '10', 'author': 'Sgonic', 'year': '1994', 'journal-title': 'Trends Genet'}
/ Trends Genet / Simultaneous determination of cell surface antigens and apoptosis by Sgonic (1994)10.1242/dev.120.10.2991
/ Development / Developmental expression of the mouse c-relproto-oncogene in hematopoietic organs by Carrasco (1994)10.1242/dev.118.4.1221
/ Development / Expression of relBtranscripts during lymphoid organ development: specific expression in dendritic antigen-presenting cells by Carrasco (1993){'key': '2023072507143220100_B36', 'first-page': '83', 'article-title': 'Differentiation of the mammalian hepatic primordium in vitro. I. Morphogenesis and the onset of hematopoiesis', 'volume': '30', 'author': 'Johnson', 'year': '1973', 'journal-title': 'J Embryol Exp Morphol'}
/ J Embryol Exp Morphol / Differentiation of the mammalian hepatic primordium in vitro. I. Morphogenesis and the onset of hematopoiesis by Johnson (1973)10.1016/0167-5699(96)10019-0
/ Immunol Today / Transcriptional control of lymphoid development: lessons from gene targeting by Clevers (1996)10.1126/science.8160012
/ Science (Wash DC) / The role of interleukin-6 in mucosal IgA antibody responses in vivo. by Ramsay (1994)10.1128/MCB.15.8.4260
/ Mol Cell Biol / RelA is a potent transcriptional activator of the CD28 response element within the interleukin 2 promoter by Lai (1995)10.1002/j.1460-2075.1995.tb00188.x
/ EMBO (Eur Mol Biol Organ) J / In vivoregulation of interleukin-2 receptor α gene transcription by the coordinated binding of constitutive and inducible factors in human primary T cells by Algarte (1995)10.1073/pnas.93.8.3405
/ Proc Natl Acad Sci USA / Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony stimulating factor by Gerondakis (1996)10.1111/j.1600-065X.1990.tb00566.x
/ Immunol Rev / Accessory cell signals involved in T-cell activation by Geppert (1990)10.1016/S0065-2776(08)60511-8
/ Adv Immunol / Biochemistry of B lymphocyte activation by Gold (1994){'key': '2023072507143220100_B44', 'first-page': '245', 'article-title': 'The murine c-relproto-oncogene encodes two mRNAs the expression of which is modulated by lymphoid stimuli', 'volume': '5', 'author': 'Grumont', 'year': '1990', 'journal-title': 'Oncogene Res'}
/ Oncogene Res / The murine c-relproto-oncogene encodes two mRNAs the expression of which is modulated by lymphoid stimuli by Grumont (1990)
Dates
Type | When |
---|---|
Created | 23 years, 1 month ago (July 26, 2002, 12:49 p.m.) |
Deposited | 2 years, 1 month ago (July 25, 2023, 3:51 a.m.) |
Indexed | 1 month, 4 weeks ago (July 2, 2025, 3:31 a.m.) |
Issued | 28 years, 5 months ago (March 3, 1997) |
Published | 28 years, 5 months ago (March 3, 1997) |
Published Online | 28 years, 5 months ago (March 3, 1997) |
Published Print | 28 years, 5 months ago (March 3, 1997) |
@article{Doi_1997, title={NF-κB RelA-deficient Lymphocytes: Normal Development of T Cells and B Cells, Impaired Production of IgA and IgG1 and Reduced Proliferative Responses}, volume={185}, ISSN={1540-9538}, url={http://dx.doi.org/10.1084/jem.185.5.953}, DOI={10.1084/jem.185.5.953}, number={5}, journal={The Journal of Experimental Medicine}, publisher={Rockefeller University Press}, author={Doi, Takahiro S. and Takahashi, Toshitada and Taguchi, Osamu and Azuma, Takachika and Obata, Yuichi}, year={1997}, month=mar, pages={953–962} }