Home LiteratureArticle Details
PMID: 12093869 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Induction of NFATc2 expression by interleukin 6 promotes T helper type 2 differentiation.

The Journal of experimental medicine ·Vol. 196 ·No. 1 ·2002-07-01 ·Pages 39-49

Diehl S, Chow CW, Weiss L, Palmetshofer A, Twardzik T, Rounds L, Serfling E, Davis RJ, Anguita J, Rincón M

Abstract

Interleukin (IL)-6 is produced by professional antigen-presenting cells (APCs) such as B cells, macrophages, and dendritic cells. It has been previously shown that APC-derived IL-6 promotes the differentiation of naive CD4+ T cells into effector T helper type 2 (Th2) cells. Here, we have studied the molecular mechanism for IL-6-mediated Th2 differentiation. During the activation of CD4+ T cells, IL-6 induces the production of IL-4, which promotes the differentiation of these cells into effector Th2 cells. Regulation of IL-4 gene expression by IL-6 is mediated by nuclear factor of activated T cells (NFAT), as inhibition of NFAT prevents IL-6-driven IL-4 production and Th2 differentiation. IL-6 upregulates NFAT transcriptional activity by increasing the levels of NFATc2. The ability of IL-6 to promote Th2 differentiation is impaired in CD4+ T cells that lack NFATc2, demonstrating that NFATc2 is required for regulation of IL-4 gene expression by IL-6. Regulation of NFATc2 expression and NFAT transcriptional activity represents a novel pathway by which IL-6 can modulate gene expression.

MeSH Terms
Animals Antigen-Presenting Cells/metabolism Cell Differentiation/drug effects,immunology DNA-Binding Proteins/deficiency,genetics,metabolism Gene Expression Regulation/drug effects,immunology Genes, Dominant Interleukin-4/genetics,metabolism Interleukin-6/biosynthesis,pharmacology Lymphocyte Activation/drug effects,physiology Mice Mice, Inbred C57BL Mice, Transgenic NFATC Transcription Factors Nuclear Proteins RNA, Messenger/metabolism Th2 Cells/cytology,drug effects,immunology Transcription Factors/deficiency,genetics,metabolism Up-Regulation/drug effects
Chemicals
DNA-Binding Proteins Interleukin-6 NFATC Transcription Factors NFATC2 protein, human Nfatc2 protein, mouse Nuclear Proteins RNA, Messenger Transcription Factors Interleukin-4
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Diehl Sean
Immunobiology Program, Department of Medicine, Given Medical Building, University of Vermont, Burlington, VT 05405, USA.
Chow Chi-Wing
Weiss Linda
Palmetshofer Alois
Twardzik Thomas
Rounds Laura
Serfling Edgar
Davis Roger J
Anguita Juan
Rincón Mercedes
References (49)
49 references, click to expand
  1. Inhibition of NF-kappaB activity and enhancement of apoptosis by the neuropeptide calcitonin gene-related peptide.
    J Biol Chem. 2000 May 19;275(20):15114-21 PMID: 10809748
  2. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells.
    Cell. 1997 May 16;89(4):587-96 PMID: 9160750
  3. c-Jun NH(2)-terminal kinase inhibits targeting of the protein phosphatase calcineurin to NFATc1.
    Mol Cell Biol. 2000 Jul;20(14):5227-34 PMID: 10866678
  4. Cell-type-restricted binding of the transcription factor NFAT to a distal IL-4 enhancer in vivo.
    Immunity. 2000 Jun;12(6):643-52 PMID: 10894164
  5. Cutting edge: chromatin remodeling at the IL-4/IL-13 intergenic regulatory region for Th2-specific cytokine gene cluster.
    J Immunol. 2000 Dec 15;165(12):6687-91 PMID: 11120785
  6. Inhibition of Th1 differentiation by IL-6 is mediated by SOCS1.
    Immunity. 2000 Dec;13(6):805-15 PMID: 11163196
  7. Activation of p38 MAP kinase in T cells facilitates the immune response to the influenza virus.
    Mol Immunol. 2000 Jun;37(9):503-13 PMID: 11163400
  8. NFATc1 and NFATc2 together control both T and B cell activation and differentiation.
    Immunity. 2001 Jan;14(1):13-20 PMID: 11163226
  9. Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells.
    Cancer Res. 2001 Dec 15;61(24):8851-8 PMID: 11751408
  10. Phorbol ester-inducible genes contain a common cis element recognized by a TPA-modulated trans-acting factor.
    Cell. 1987 Jun 19;49(6):729-39 PMID: 3034432
  11. Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements.
    Cell. 1987 Jun 19;49(6):741-52 PMID: 3034433
  12. Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene.
    Nature. 1987 Jul 9-15;328(6126):175-8 PMID: 2885756
  13. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130.
    Cell. 1989 Aug 11;58(3):573-81 PMID: 2788034
  14. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells.
    Nucleic Acids Res. 1989 Aug 11;17(15):6419 PMID: 2771659
  15. A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family.
    EMBO J. 1990 Jun;9(6):1897-906 PMID: 2112087
  16. IL-6DBP, a nuclear protein involved in interleukin-6 signal transduction, defines a new family of leucine zipper proteins related to C/EBP.
    Cell. 1990 Nov 2;63(3):643-53 PMID: 2171780
  17. A member of the C/EBP family, NF-IL6 beta, forms a heterodimer and transcriptionally synergizes with NF-IL6.
    Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1473-6 PMID: 1741402
  18. Activation-induced inhibition of interleukin 6-mediated T cell survival and signal transducer and activator of transcription 1 signaling.
    J Exp Med. 2000 Mar 20;191(6):915-26 PMID: 10727454
  19. Human T cell activation through the activation-inducer molecule/CD69 enhances the activity of transcription factor AP-1.
    J Immunol. 1992 Apr 1;148(7):2300-6 PMID: 1545132
  20. The two C/EBP isoforms, IL-6DBP/NF-IL6 and C/EBP delta/NF-IL6 beta, are induced by IL-6 to promote acute phase gene transcription via different mechanisms.
    Nucleic Acids Res. 1993 Jan 25;21(2):289-94 PMID: 7680115
  21. Recombinant IL-6 activates p42 and p44 mitogen-activated protein kinases in the IL-6 responsive B cell line, AF-10.
    J Immunol. 1993 Jun 1;150(11):4743-53 PMID: 8388418
  22. Identification of cis-acting regulatory elements controlling interleukin-4 gene expression in T cells: roles for NF-Y and NF-ATc.
    Mol Cell Biol. 1993 Aug;13(8):4793-805 PMID: 8336717
  23. Isolation of the cyclosporin-sensitive T cell transcription factor NFATp.
    Science. 1993 Oct 29;262(5134):750-4 PMID: 8235597
  24. IL-6 rescues resting mouse T cells from apoptosis.
    J Immunol. 1997 Jun 15;158(12):5791-6 PMID: 9190930
  25. NF-ATp plays a prominent role in the transcriptional induction of Th2-type lymphokines.
    Immunol Lett. 1997 Jun 1;57(1-3):171-5 PMID: 9232447
  26. Down-regulation of IL-4 gene transcription and control of Th2 cell differentiation by a mechanism involving NFAT1.
    Immunity. 1997 Dec;7(6):849-60 PMID: 9430230
  27. The transcription factor NF-ATc1 regulates lymphocyte proliferation and Th2 cytokine production.
    Immunity. 1998 Jan;8(1):115-24 PMID: 9462517
  28. Delayed lymphoid repopulation with defects in IL-4-driven responses produced by inactivation of NF-ATc.
    Immunity. 1998 Jan;8(1):125-34 PMID: 9462518
  29. Interleukin 6 and its receptor: ten years later.
    Int Rev Immunol. 1998;16(3-4):249-84 PMID: 9505191
  30. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway.
    Biochem J. 1998 Sep 1;334 ( Pt 2):297-314 PMID: 9716487
  31. The transcription factor NFAT4 is involved in the generation and survival of T cells.
    Immunity. 1998 Sep;9(3):295-304 PMID: 9768749
  32. The role of C/EBP isoforms in the control of inflammatory and native immunity functions.
    J Biol Chem. 1998 Nov 6;273(45):29279-82 PMID: 9792624
  33. Inhibitory function of two NFAT family members in lymphoid homeostasis and Th2 development.
    Immunity. 1998 Nov;9(5):627-35 PMID: 9846484
  34. Inhibition of Th1 development mediated by GATA-3 through an IL-4-independent mechanism.
    Immunity. 1998 Nov;9(5):745-55 PMID: 9846495
  35. Requirement for transcription factor NFAT in interleukin-2 expression.
    Mol Cell Biol. 1999 Mar;19(3):2300-7 PMID: 10022916
  36. Association of transcription factor APRF and protein kinase Jak1 with the interleukin-6 signal transducer gp130.
    Science. 1994 Jan 7;263(5143):89-92 PMID: 8272872
  37. Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 beta receptor components.
    Science. 1994 Jan 7;263(5143):92-5 PMID: 8272873
  38. Multiple closely-linked NFAT/octamer and HMG I(Y) binding sites are part of the interleukin-4 promoter.
    Nucleic Acids Res. 1993 Dec 11;21(24):5694-704 PMID: 8284217
  39. A common factor regulates both Th1- and Th2-specific cytokine gene expression.
    EMBO J. 1994 Feb 1;13(3):625-33 PMID: 8313907
  40. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway.
    Cell. 1994 Apr 8;77(1):63-71 PMID: 7512451
  41. NF-AT components define a family of transcription factors targeted in T-cell activation.
    Nature. 1994 Jun 9;369(6480):497-502 PMID: 8202141
  42. AP-1 transcriptional activity requires both T-cell receptor-mediated and co-stimulatory signals in primary T lymphocytes.
    EMBO J. 1994 Sep 15;13(18):4370-81 PMID: 7925281
  43. Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene.
    Immunity. 1995 May;2(5):473-83 PMID: 7749982
  44. Signal transduction through IL-6 receptor: involvement of multiple protein kinases, stat factors, and a novel H7-sensitive pathway.
    Ann N Y Acad Sci. 1995 Jul 21;762:55-70 PMID: 7545378
  45. Regulation of AP-1 and NFAT transcription factors during thymic selection of T cells.
    Mol Cell Biol. 1996 Mar;16(3):1074-84 PMID: 8622652
  46. Hyperproliferation and dysregulation of IL-4 expression in NF-ATp-deficient mice.
    Immunity. 1996 Apr;4(4):397-405 PMID: 8612134
  47. Transcription mediated by NFAT is highly inducible in effector CD4+ T helper 2 (Th2) cells but not in Th1 cells.
    Mol Cell Biol. 1997 Mar;17(3):1522-34 PMID: 9032280
  48. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells.
    J Exp Med. 1997 Feb 3;185(3):461-9 PMID: 9053446
  49. Signaling and transcription in T helper development.
    Annu Rev Immunol. 2000;18:451-94 PMID: 10837066
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20020026
Published
2002-07-01
Pages
39-49
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2194007
Subset
IM
Grants
NCRR NIH HHS · P20 RR015557 · United States
NIEHS NIH HHS · T32 ES007122 · United States
NIEHS NIH HHS · T32ES07122 · United States
NCRR NIH HHS · P20 RR 15557 · United States
NIAID NIH HHS · P01 AI045666 · United States
NIAID NIH HHS · P01 AI45666 · United States
External Links
PubMed source DOI: 10.1084/jem.20020026 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