Home LiteratureArticle Details
PMID: 8622948 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Rel-deficient T cells exhibit defects in production of interleukin 3 and granulocyte-macrophage colony-stimulating factor.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 93 ·No. 8 ·1996-04-16 ·Pages 3405-9

Gerondakis S, Strasser A, Metcalf D, Grigoriadis G, Scheerlinck JY, Grumont RJ

Abstract

The c-rel protooncogene encodes a subunit of the NF-kappa B-like family of transcription factors. Mice lacking Rel are defective in mitogenic activation of B and T lymphocytes and display impaired humoral immunity. In an attempt to identify changes in gene expression that accompany the T-cell stimulation defects associated with the loss of Rel, we have examined the expression of cell surface activation markers and cytokine production in mitogen-stimulated Rel-/- T cells. The expression of cell surface markers including the interleukin 2 receptor alpha (IL-2R alpha) chain (CD25), CD69 and L-selectin (CD62) is normal in mitogen-activated Rel-/- T cells, but cytokine production is impaired. In Rel-/- splenic T cell cultures stimulated with phorbol 12-myristate 13-acetate and ionomycin, the levels of IL-3, IL-5, granulocyte- macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNF-alpha), and gamma interferon (IFN-gamma) were only 2- to 3-fold lower compared with normal T cells. In contrast, anti-CD3 and anti-CD28 stimulated Rel-/- T cells, which fail to proliferate, make little or no detectable cytokines. Exogenous IL-2, which restitutes the proliferative response of the anti-CD3- and anti-CD28-treated Rel-/- T cells, restores production of IL-5, TNF-alpha, and IFN-gamma, but not IL-3 and GM-CSF expression to approximately normal levels. In contrast to mitogen-activated Rel-/- T cells, lipopolysaccharide-stimulated Rel-/- macrophages produce higher than normal levels of GM-CSF. These findings establish that Rel can function as an activator or repressor of gene expression and is required by T lymphocytes for production of IL-3 and GM-CSF.

MeSH Terms
Animals Antigens, Differentiation, T-Lymphocyte/genetics Base Sequence Binding Sites/genetics Cytokines/biosynthesis DNA/genetics,metabolism Gene Expression/drug effects Granulocyte-Macrophage Colony-Stimulating Factor/biosynthesis Humans Interleukin-3/biosynthesis Macrophages/immunology,metabolism Mice Mitogens/pharmacology Molecular Sequence Data NF-kappa B/metabolism Proto-Oncogene Proteins/deficiency,genetics Proto-Oncogene Proteins c-rel T-Lymphocytes/immunology,metabolism Transcription Factors/deficiency,genetics
Chemicals
Antigens, Differentiation, T-Lymphocyte Cytokines Interleukin-3 Mitogens NF-kappa B Proto-Oncogene Proteins Proto-Oncogene Proteins c-rel Transcription Factors Granulocyte-Macrophage Colony-Stimulating Factor DNA
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Gerondakis S
The Walter and Eliza Hall Institute of Medical Research, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
Strasser A
Metcalf D
Grigoriadis G
Scheerlinck J Y
Grumont R J
References (44)
44 references, click to expand
  1. Structure, regulation and function of NF-kappa B.
    Annu Rev Cell Biol. 1994;10:405-55 PMID: 7888182
  2. FK506 inhibits antigen receptor-mediated induction of c-rel in B and T lymphoid cells.
    J Exp Med. 1995 Mar 1;181(3):1091-9 PMID: 7532676
  3. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression.
    Genes Dev. 1995 Aug 15;9(16):1965-77 PMID: 7649478
  4. Mechanistic aspects of NF-kappa B regulation: the emerging role of phosphorylation and proteolysis.
    Immunity. 1995 Sep;3(3):263-72 PMID: 7552992
  5. Kappa B-specific DNA binding proteins: role in the regulation of human interleukin-2 gene expression.
    Science. 1989 Apr 28;244(4903):457-60 PMID: 2497518
  6. Monoclonal antibody-mediated tumor regression by induction of apoptosis.
    Science. 1989 Jul 21;245(4915):301-5 PMID: 2787530
  7. The murine c-rel proto-oncogene encodes two mRNAs the expression of which is modulated by lymphoid stimuli.
    Oncogene Res. 1990;5(4):245-54 PMID: 2204017
  8. Frequency analysis of lymphokine-secreting CD4+ and CD8+ T cells activated in a graft-versus-host reaction.
    J Immunol. 1990 Oct 1;145(7):2167-76 PMID: 1975827
  9. Regulation of interleukin-2 gene enhancer activity by the T cell accessory molecule CD28.
    Science. 1991 Jan 18;251(4991):313-6 PMID: 1846244
  10. Murine c-rel transcription is rapidly induced in T-cells and fibroblasts by mitogenic agents and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate.
    Cell Growth Differ. 1990 Aug;1(8):345-50 PMID: 2278886
  11. The inducible transcription activator NF-kappa B: regulation by distinct protein subunits.
    Biochim Biophys Acta. 1991 Apr 16;1072(1):63-80 PMID: 2018779
  12. Multi-CSF-dependent colony formation by cells of a murine hemopoietic cell line: specificity and action of multi-CSF.
    Blood. 1985 Feb;65(2):357-62 PMID: 3881141
  13. Identification of a monoclonal antibody specific for a murine T3 polypeptide.
    Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374-8 PMID: 2950524
  14. The human IL-2 receptor gene contains a positive regulatory element that functions in cultured cells and cell-free extracts.
    J Biol Chem. 1987 Apr 15;262(11):5079-86 PMID: 3031040
  15. Detection of c-rel-related transcripts in mouse hematopoietic tissues, fractionated lymphocyte populations, and cell lines.
    Mol Cell Biol. 1987 Mar;7(3):1304-9 PMID: 2436042
  16. Nuclear proteins interacting with the promoter region of the human granulocyte/macrophage colony-stimulating factor gene.
    Proc Natl Acad Sci U S A. 1988 Feb;85(3):674-8 PMID: 3257571
  17. Molecular analysis of dorsal-ventral polarity in Drosophila.
    Cell. 1988 Mar 25;52(6):785-6 PMID: 3280135
  18. Contingent genetic regulatory events in T lymphocyte activation.
    Science. 1989 Jan 20;243(4889):355-61 PMID: 2783497
  19. CD28 activation pathway regulates the production of multiple T-cell-derived lymphokines/cytokines.
    Proc Natl Acad Sci U S A. 1989 Feb;86(4):1333-7 PMID: 2465550
  20. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis.
    Cell. 1991 Jul 26;66(2):233-43 PMID: 1713127
  21. bcl-2 transgene inhibits T cell death and perturbs thymic self-censorship.
    Cell. 1991 Nov 29;67(5):889-99 PMID: 1959134
  22. Malignant transformation by mutant Rel proteins.
    Trends Genet. 1991 Oct;7(10):318-22 PMID: 1781029
  23. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones.
    Nature. 1992 Apr 16;356(6370):607-9 PMID: 1313950
  24. The inhibitory ankyrin and activator Rel proteins.
    Curr Opin Genet Dev. 1992 Apr;2(2):211-20 PMID: 1386268
  25. Kappa B site-dependent activation of the interleukin-2 receptor alpha-chain gene promoter by human c-Rel.
    Mol Cell Biol. 1992 Sep;12(9):4067-75 PMID: 1508203
  26. Stimulation of mature unprimed CD8+ T cells by semiprofessional antigen-presenting cells in vivo.
    J Exp Med. 1992 Nov 1;176(5):1291-302 PMID: 1402675
  27. Selection of optimal kappa B/Rel DNA-binding motifs: interaction of both subunits of NF-kappa B with DNA is required for transcriptional activation.
    Mol Cell Biol. 1992 Oct;12(10):4412-21 PMID: 1406630
  28. The high mobility group protein HMG I(Y) is required for NF-kappa B-dependent virus induction of the human IFN-beta gene.
    Cell. 1992 Nov 27;71(5):777-89 PMID: 1330326
  29. The interleukin 2 CD28-responsive complex contains at least three members of the NF kappa B family: c-Rel, p50, and p65.
    Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1696-700 PMID: 8383323
  30. NF-kappa B and Rel: participants in a multiform transcriptional regulatory system.
    Int Rev Cytol. 1993;143:1-62 PMID: 8449662
  31. Leukemic transformation of immortalized FDC-P1 cells engrafted in GM-CSF transgenic mice.
    Leukemia. 1993 Jun;7(6):878-86 PMID: 8501982
  32. Cyclic AMP-independent ATF family members interact with NF-kappa B and function in the activation of the E-selectin promoter in response to cytokines.
    Mol Cell Biol. 1993 Nov;13(11):7180-90 PMID: 7692236
  33. Distinct mechanisms for regulation of the interleukin-8 gene involve synergism and cooperativity between C/EBP and NF-kappa B.
    Mol Cell Biol. 1993 Nov;13(11):7191-8 PMID: 8413306
  34. Activation and differentiation requirements of primary T cells in vitro.
    Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):8987-91 PMID: 8415642
  35. A cooperative interaction between NF-kappa B and Sp1 is required for HIV-1 enhancer activation.
    EMBO J. 1993 Sep;12(9):3551-8 PMID: 8253080
  36. v-rel induces expression of three avian immunoregulatory surface receptors more efficiently than c-rel.
    J Virol. 1994 Jan;68(1):308-19 PMID: 8254742
  37. Qualitative changes in the subunit composition of kappa B-binding complexes during murine B-cell differentiation.
    Proc Natl Acad Sci U S A. 1994 May 24;91(11):5056-60 PMID: 8197184
  38. Function and activation of NF-kappa B in the immune system.
    Annu Rev Immunol. 1994;12:141-79 PMID: 8011280
  39. Sequential induction of NF-kappa B/Rel family proteins during B-cell terminal differentiation.
    Mol Cell Biol. 1994 Aug;14(8):5349-59 PMID: 8035813
  40. An HMG-like protein that can switch a transcriptional activator to a repressor.
    Nature. 1994 Sep 8;371(6493):175-9 PMID: 8072548
  41. Activation of naive, memory and effector T cells.
    Curr Opin Immunol. 1994 Jun;6(3):431-7 PMID: 7917111
  42. Effect of CD28 signal transduction on c-Rel in human peripheral blood T cells.
    Mol Cell Biol. 1994 Dec;14(12):7933-42 PMID: 7969133
  43. Signal transmission between the plasma membrane and nucleus of T lymphocytes.
    Annu Rev Biochem. 1994;63:1045-83 PMID: 7979236
  44. The subunit composition of NF-kappa B complexes changes during B-cell development.
    Cell Growth Differ. 1994 Dec;5(12):1321-31 PMID: 7696180
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.93.8.3405
Published
1996-04-16
Pages
3405-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC39621
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.93.8.3405 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2