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CD40 induces interleukin-6 gene transcription in dendritic cells: regulation by TRAF2, AP-1, NF-kappa B, AND CBF1.
J Biol Chem. 2002 May 10; 277(19):17125-38.JB

Abstract

CD40-induced activation of cytokine gene expression in dendritic cells (DC) is an important process in the initiation of primary immune responses. We have determined the intracellular signaling events that lead to CD40 ligation-induced activation of interleukin-6 (IL-6) gene transcription in a murine DC line, FSDC, that is phenotypically representative of bone marrow-derived DC. IL-6 reverse transcriptase-PCR and promoter assays established the responsiveness of FSDC to anti-CD40 ligation. Further promoter assays showed that the transcription factors NF-kappaB and AP-1 are downstream transcriptional mediators of CD40-induced IL-6 gene expression. Anti-CD40 treatment of FSDC stimulated increased expression of specific NF-kappaB (p50:p65) and AP-1 (c-Jun, JunB, JunD, and c-Fos) DNA-protein complexes. Overexpression of an IkappaB-alpha super-repressor or a dominant negative JunD resulted in a strong inhibition of CD40-inducible IL-6 promoter activity supporting a role for both transcription factors. Upstream signal transduction events were studied by transfection of wild type and mutant human CD40 expression constructs into FSDC followed by stimulation with an anti-human CD40 antibody. These experiments revealed that anti-CD40 stimulation of NF-kappaB and IL-6 gene transcription requires specific amino acid residues in the cytoplasmic region of CD40 involved in the recruitment of TRAF2. Induction of IL-6 mRNA by anti-CD40 treatment was found to be a transient event (24 h) and was followed by a diminution of IL-6 transcript to levels below those found in unstimulated cells. This loss of IL-6 expression was associated with reduced p50:p65 NF-kappaB DNA binding and elevated binding of CBF1 to a site overlapping the NF-kappaB site. Overexpression of CBF1 resulted in a profound inhibition of basal and anti-CD40-induced IL-6 promoter activities indicating that prolonged induction of CBF1 may contribute to the transient nature of the IL-6 response. The physiological relevance of these molecular events to DC function is discussed.

Authors+Show Affiliations

Division of Infection, Inflammation and Repair and Division of Cancer Sciences, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11886848

Citation

Mann, Jelena, et al. "CD40 Induces Interleukin-6 Gene Transcription in Dendritic Cells: Regulation By TRAF2, AP-1, NF-kappa B, and CBF1." The Journal of Biological Chemistry, vol. 277, no. 19, 2002, pp. 17125-38.
Mann J, Oakley F, Johnson PW, et al. CD40 induces interleukin-6 gene transcription in dendritic cells: regulation by TRAF2, AP-1, NF-kappa B, AND CBF1. J Biol Chem. 2002;277(19):17125-38.
Mann, J., Oakley, F., Johnson, P. W., & Mann, D. A. (2002). CD40 induces interleukin-6 gene transcription in dendritic cells: regulation by TRAF2, AP-1, NF-kappa B, AND CBF1. The Journal of Biological Chemistry, 277(19), 17125-38.
Mann J, et al. CD40 Induces Interleukin-6 Gene Transcription in Dendritic Cells: Regulation By TRAF2, AP-1, NF-kappa B, and CBF1. J Biol Chem. 2002 May 10;277(19):17125-38. PubMed PMID: 11886848.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CD40 induces interleukin-6 gene transcription in dendritic cells: regulation by TRAF2, AP-1, NF-kappa B, AND CBF1. AU - Mann,Jelena, AU - Oakley,Fiona, AU - Johnson,Peter W M, AU - Mann,Derek A, Y1 - 2002/03/08/ PY - 2002/3/12/pubmed PY - 2002/6/14/medline PY - 2002/3/12/entrez SP - 17125 EP - 38 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 277 IS - 19 N2 - CD40-induced activation of cytokine gene expression in dendritic cells (DC) is an important process in the initiation of primary immune responses. We have determined the intracellular signaling events that lead to CD40 ligation-induced activation of interleukin-6 (IL-6) gene transcription in a murine DC line, FSDC, that is phenotypically representative of bone marrow-derived DC. IL-6 reverse transcriptase-PCR and promoter assays established the responsiveness of FSDC to anti-CD40 ligation. Further promoter assays showed that the transcription factors NF-kappaB and AP-1 are downstream transcriptional mediators of CD40-induced IL-6 gene expression. Anti-CD40 treatment of FSDC stimulated increased expression of specific NF-kappaB (p50:p65) and AP-1 (c-Jun, JunB, JunD, and c-Fos) DNA-protein complexes. Overexpression of an IkappaB-alpha super-repressor or a dominant negative JunD resulted in a strong inhibition of CD40-inducible IL-6 promoter activity supporting a role for both transcription factors. Upstream signal transduction events were studied by transfection of wild type and mutant human CD40 expression constructs into FSDC followed by stimulation with an anti-human CD40 antibody. These experiments revealed that anti-CD40 stimulation of NF-kappaB and IL-6 gene transcription requires specific amino acid residues in the cytoplasmic region of CD40 involved in the recruitment of TRAF2. Induction of IL-6 mRNA by anti-CD40 treatment was found to be a transient event (24 h) and was followed by a diminution of IL-6 transcript to levels below those found in unstimulated cells. This loss of IL-6 expression was associated with reduced p50:p65 NF-kappaB DNA binding and elevated binding of CBF1 to a site overlapping the NF-kappaB site. Overexpression of CBF1 resulted in a profound inhibition of basal and anti-CD40-induced IL-6 promoter activities indicating that prolonged induction of CBF1 may contribute to the transient nature of the IL-6 response. The physiological relevance of these molecular events to DC function is discussed. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/11886848/CD40_induces_interleukin_6_gene_transcription_in_dendritic_cells:_regulation_by_TRAF2_AP_1_NF_kappa_B_AND_CBF1_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=11886848 DB - PRIME DP - Unbound Medicine ER -