The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells

Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4+ T cells upon T cell receptor stimulation. IL-21 production by CD4+ T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4+ T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.

[1]  D. Hwang,et al.  Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. , 2008, Immunity.

[2]  T. Nakayama,et al.  Development and characterization of IL-21–producing CD4+ T cells , 2008, The Journal of experimental medicine.

[3]  Hergen Spits,et al.  STAT3-Mediated Up-Regulation of BLIMP1 Is Coordinated with BCL6 Down-Regulation to Control Human Plasma Cell Differentiation1 , 2008, The Journal of Immunology.

[4]  H. Asada,et al.  IL-21 Induces Inhibitor of Differentiation 2 and Leads to Complete Abrogation of Anaphylaxis in Mice1 , 2007, The Journal of Immunology.

[5]  Lai Wei,et al.  IL-21 Is Produced by Th17 Cells and Drives IL-17 Production in a STAT3-dependent Manner* , 2007, Journal of Biological Chemistry.

[6]  D. Levy,et al.  IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways , 2007, Nature Immunology.

[7]  Terry B. Strom,et al.  IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells , 2007, Nature.

[8]  A. D. Panopoulos,et al.  Essential autocrine regulation by IL-21 in the generation of inflammatory T cells , 2007, Nature.

[9]  R. Locksley,et al.  IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge , 2007, Nature Immunology.

[10]  Chen Dong,et al.  STAT3 Regulates Cytokine-mediated Generation of Inflammatory Helper T Cells* , 2007, Journal of Biological Chemistry.

[11]  Mark J. Smyth,et al.  IL-21 Is Produced by NKT Cells and Modulates NKT Cell Activation and Cytokine Production1 , 2007, The Journal of Immunology.

[12]  D. Littman,et al.  The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells , 2006, Cell.

[13]  H. Weiner,et al.  Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells , 2006, Nature.

[14]  R. D. Hatton,et al.  Transforming growth factor-β induces development of the TH17 lineage , 2006, Nature.

[15]  V. Poli,et al.  Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells. , 2006, Blood.

[16]  R. J. Hocking,et al.  TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. , 2006, Immunity.

[17]  P. Lipsky,et al.  IL-21 Induces Differentiation of Human Naive and Memory B Cells into Antibody-Secreting Plasma Cells1 , 2005, The Journal of Immunology.

[18]  Simon A. Jones,et al.  Directing Transition from Innate to Acquired Immunity: Defining a Role for IL-61 , 2005, The Journal of Immunology.

[19]  W. Leonard,et al.  Interleukin-21: a modulator of lymphoid proliferation, apoptosis and differentiation , 2005, Nature Reviews Immunology.

[20]  J. Ochando,et al.  IL-6 Plays a Unique Role in Initiating c-Maf Expression during Early Stage of CD4 T Cell Activation1 , 2005, The Journal of Immunology.

[21]  P. Lipsky,et al.  Regulation of B Cell Differentiation and Plasma Cell Generation by IL-21, a Novel Inducer of Blimp-1 and Bcl-61 , 2004, The Journal of Immunology.

[22]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[23]  C. Mackay,et al.  T Follicular Helper Cells Express a Distinctive Transcriptional Profile, Reflecting Their Role as Non-Th1/Th2 Effector Cells That Provide Help for B Cells1 , 2004, The Journal of Immunology.

[24]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[25]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[26]  M. Rincón,et al.  The two faces of IL-6 on Th1/Th2 differentiation. , 2002, Molecular immunology.

[27]  A. Sher,et al.  A Critical Role for IL-21 in Regulating Immunoglobulin Production , 2002, Science.

[28]  A. Satoskar,et al.  Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon γ–producing Th1 Cells , 2002, The Journal of experimental medicine.

[29]  S. Knudsen,et al.  A new non-linear normalization method for reducing variability in DNA microarray experiments , 2002, Genome Biology.

[30]  E. Serfling,et al.  Induction of NFATc2 Expression by Interleukin 6 Promotes T Helper Type 2 Differentiation , 2002, The Journal of experimental medicine.

[31]  P. Rogers,et al.  Qualitative Changes Accompany Memory T Cell Generation: Faster, More Effective Responses at Lower Doses of Antigen1 , 2000, The Journal of Immunology.

[32]  R. Jove,et al.  Inhibition of pp60c-Src reduces Bcl-XL expression and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors , 1999, Oncogene.

[33]  M. Wiles,et al.  Interleukin 6 Influences Germinal Center Development and Antibody Production via a Contribution of C3 Complement Component , 1998, The Journal of experimental medicine.

[34]  T. Kishimoto,et al.  Impairment of antigen-specific antibody production in transgenic mice expressing a dominant-negative form of gp130. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[35]  R. Flavell,et al.  Transcription mediated by NFAT is highly inducible in effector CD4+ T helper 2 (Th2) cells but not in Th1 cells , 1997, Molecular and cellular biology.

[36]  E. Fikrig,et al.  Interleukin (IL)-6 Directs the Differentiation of IL-4–producing CD4+ T Cells , 1997, The Journal of experimental medicine.

[37]  G. Ciliberto,et al.  Interleukin‐6 deficient mice are protected from bone loss caused by estrogen depletion. , 1994, The EMBO journal.

[38]  S. Jameson,et al.  Selective development of CD4+ T cells in transgenic mice expressing a class II MHC-restricted antigen receptor , 1989, Nature.

[39]  J. Miyazaki,et al.  IgG1 plasmacytosis in interleukin 6 transgenic mice. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[40]  T. Hirano,et al.  Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[41]  T. Kishimoto.  Interleukin-6: from basic science to medicine--40 years in immunology. , 2005, Annual review of immunology.

[42]  T. Hirano,et al.  IL-6 signal transduction and its physiological roles: the signal orchestration model. , 2003, Reviews of physiology, biochemistry and pharmacology.