Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus-prone B6.Sle1.Yaa animals.

We previously reported the inhibitory action of interleukin-6 (IL-6) on B lymphopoiesis with SHIP(-/-) mice and showed that IL-6 biases lineage commitment toward myeloid cell fates in vitro and in vivo. Because elevated IL-6 is a feature of chronic inflammatory diseases, we applied an animal model of systemic lupus erythematosus (SLE) to determine whether IL-6 has similar effects on hematopoiesis. We found that IL-6 levels were elevated in the B6.Sle1.Yaa mice, and the increase was accompanied by losses of CD19(+) B cells and more primitive B-lymphoid progenitors in bone marrow. Both the CD19(+) B-cell population and their progenitors recovered in an IL-6(-/-) background. The uncommitted progenitors, containing precursors for both lymphoid and myeloid fates, expressed IL-6 receptor-alpha chain and responded to IL-6 by phosphorylation of STAT3. IL-6 stimulation caused uncommitted progenitors to express the Id1 transcription factor, which is known to inhibit lymphopoiesis and elevate myelopoiesis, and its expression was MAPK dependent. We conclude that chronic inflammatory conditions accompanied by increased IL-6 production bias uncommitted progenitors to a myeloid fate by inducing Id1 expression.

[1]  C. Quilici,et al.  “Emergency” granulopoiesis in G-CSF–deficient mice in response to Candida albicans infection , 2000 .

[2]  C. Cheers,et al.  Essential Roles for Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and G-CSF in the Sustained Hematopoietic Response ofListeria monocytogenes–Infected Mice , 1998 .

[3]  Xiao-Hong Sun Constitutive expression of the Id1 gene impairs mouse B cell development , 1994, Cell.

[4]  H. Takano,et al.  Role of interleukin-6 in bleomycin-induced lung inflammatory changes in mice. , 2008, American journal of respiratory cell and molecular biology.

[5]  J. Darnell,et al.  Signalling: STATs: transcriptional control and biological impact , 2002, Nature Reviews Molecular Cell Biology.

[6]  B. Bresnihan,et al.  Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. , 1996, Arthritis and rheumatism.

[7]  P. Kincade,et al.  Relationships between early B- and NK-lineage lymphocyte precursors in bone marrow. , 2002, Blood.

[8]  G. Dranoff,et al.  Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites , 1998, Nature.

[9]  A. Satterthwaite,et al.  Autoreactive B Cell Responses to RNA-Related Antigens Due to TLR7 Gene Duplication , 2006, Science.

[10]  T. Miyamae,et al.  Improvement of reduced serum cartilage oligomeric matrix protein levels in systemic juvenile idiopathic arthritis patients treated with the anti-interleukin-6 receptor monoclonal antibody tocilizumab , 2009, Modern rheumatology.

[11]  I. Weissman,et al.  Identification of Clonogenic Common Lymphoid Progenitors in Mouse Bone Marrow , 1997, Cell.

[12]  Kay Ab,et al.  Asthma. Eosinophils and neutrophils. , 1992 .

[13]  M. Busslinger,et al.  Instructive role of the transcription factor E2A in early B lymphopoiesis and germinal center B cell development. , 2008, Immunity.

[14]  R. Price,et al.  Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. , 2002, Arthritis and rheumatism.

[15]  I. Weissman,et al.  Flk-2 is a marker in hematopoietic stem cell differentiation: A simple method to isolate long-term stem cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Quanzhen Li,et al.  A Tlr7 translocation accelerates systemic autoimmunity in murine lupus. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[17]  B. Croker,et al.  Genetic interactions between susceptibility loci reveal epistatic pathogenic networks in murine lupus , 2003, Genes and Immunity.

[18]  R. Atkins Macrophages in renal injury. , 1998, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[19]  D. Greaves,et al.  Atherosclerosis: role of chemokines and macrophages , 2001, Expert Reviews in Molecular Medicine.

[20]  D. Gill,et al.  Twenty-year remission of rheumatoid arthritis in 2 patients after allogeneic bone marrow transplant. , 2006, The Journal of rheumatology.

[21]  B. Cohen,et al.  Treatment of autoimmune disease by intense immunosuppressive conditioning and autologous hematopoietic stem cell transplantation. , 1998, Blood.

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

[23]  M. Pierer,et al.  B lymphocytopenia in rheumatoid arthritis is associated with the DRB1 shared epitope and increased acute phase response , 2002, Arthritis research.

[24]  K. Coggeshall,et al.  Src Homology 2–containing 5-Inositol Phosphatase (SHIP) Suppresses an Early Stage of Lymphoid Cell Development through Elevated Interleukin-6 Production by Myeloid Cells in Bone Marrow , 2004, The Journal of experimental medicine.

[25]  Y. Baba,et al.  IL-6 blocks a discrete early step in lymphopoiesis. , 2005, Blood.

[26]  C. Quilici,et al.  "Emergency" granulopoiesis in G-CSF-deficient mice in response to Candida albicans infection. , 2000, Blood.

[27]  Satoru Takahashi,et al.  The Yaa Gene Model of Systemic Lupus Erythematosus , 1995, Immunological reviews.

[28]  H. Bluethmann,et al.  Establishment of the role of IL‐6 and TNF receptor 1 using gene knockout mice , 1994, Journal of leukocyte biology.

[29]  C. Mohan,et al.  Genetic dissection of SLE pathogenesis. Sle1 on murine chromosome 1 leads to a selective loss of tolerance to H2A/H2B/DNA subnucleosomes. , 1998, The Journal of clinical investigation.

[30]  X. Sun,et al.  Regulation of the pro-B-cell-specific enhancer of the Id1 gene involves the C/EBP family of proteins , 1997, Molecular and cellular biology.

[31]  Antony W Burgess,et al.  IL6/sIL6R complex contributes to emergency granulopoietic responses in G-CSF- and GM-CSF-deficient mice. , 2008, Blood.

[32]  K. Akashi,et al.  C/EBPbeta is required for 'emergency' granulopoiesis. , 2006, Nature immunology.

[33]  F. Lemoine,et al.  Suppression of Normal Hematopoiesis during Acute Leukemias a , 1991, Annals of the New York Academy of Sciences.

[34]  M. Belosevic,et al.  Regulation of myeloid development and function by colony stimulating factors. , 2004, Developmental and comparative immunology.

[35]  J. Reveille,et al.  Systemic lupus erythematosus in a multiethnic US cohort, XXXVII: association of lymphopenia with clinical manifestations, serologic abnormalities, disease activity, and damage accrual. , 2006, Arthritis and rheumatism.

[36]  K. Khan,et al.  Characterization of promoter elements of an interferon-inducible Ly-6E/A differentiation antigen, which is expressed on activated T cells and hematopoietic stem cells , 1990, Molecular and cellular biology.

[37]  Xiao-Hong Sun Multitasking of helix-loop-helix proteins in lymphopoiesis. , 2004, Advances in immunology.

[38]  Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. , 2000 .

[39]  C. Corrigan,et al.  Eosinophils and neutrophils , 1984 .

[40]  M. Espeland,et al.  Cell populations and episodic periodontal attachment loss in humans. , 1991, Journal of clinical periodontology.

[41]  M. Nussenzweig,et al.  Immunization and Infection Change the Number of Recombination Activating Gene (Rag)-Expressing B Cells in the Periphery by Altering Immature Lymphocyte Production , 2000, The Journal of experimental medicine.

[42]  Ying Zhao,et al.  Balance between Id and E proteins regulates myeloid-versus-lymphoid lineage decisions. , 2009, Blood.

[43]  J Sullivan,et al.  Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. , 1995, International journal of radiation oncology, biology, physics.

[44]  D. Davidson,et al.  The CF mouse: an important tool for studying cystic fibrosis , 2001, Expert Reviews in Molecular Medicine.

[45]  M. Alarcón‐Riquelme,et al.  Macrophage depletion decreases IgG anti‐DNA in cultures from (NZB · NZW)F1 spleen cells by eliminating the main source of IL‐6 , 1993, Clinical and experimental immunology.

[46]  C. Corrigan,et al.  Asthma. Eosinophils and neutrophils. , 1992, British medical bulletin.

[47]  K. Blenman,et al.  The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[48]  M. Schneider Exploring new territory: considering the future , 2007, Lupus.

[49]  Y. Shima,et al.  Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. , 2000, Blood.

[50]  C. Cheers,et al.  Essential roles for granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF in the sustained hematopoietic response of Listeria monocytogenes-infected mice. , 1998, Blood.

[51]  G. Kelsoe,et al.  Inflammation Controls B Lymphopoiesis by Regulating Chemokine CXCL12 Expression , 2004, The Journal of experimental medicine.

[52]  H. Igarashi,et al.  Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. , 2002, Immunity.

[53]  E. Wakeland,et al.  The Major Murine Systemic Lupus Erythematosus Susceptibility Locus Sle1 Results in Abnormal Functions of Both B and T Cells1 , 2002, The Journal of Immunology.

[54]  H. Singh,et al.  Regulation of B lymphocyte and macrophage development by graded expression of PU.1. , 2000, Science.

[55]  P. Quesenberry,et al.  Expression of the Id family helix-loop-helix regulators during growth and development in the hematopoietic system. , 1997, Blood.

[56]  T. Hibi,et al.  A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. , 2004, Gastroenterology.

[57]  E. Werner,et al.  Immune activation and the anaemia associated with chronic inflammatory disorders , 1991, European journal of haematology.

[58]  M. Genovese,et al.  Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. , 2008, Arthritis and rheumatism.

[59]  C. Trautwein,et al.  Signal transducer of inflammation gp130 modulates atherosclerosis in mice and man , 2007, The Journal of experimental medicine.

[60]  Lina A. Thoren,et al.  Identification of Flt3+ Lympho-Myeloid Stem Cells Lacking Erythro-Megakaryocytic Potential A Revised Road Map for Adult Blood Lineage Commitment , 2005, Cell.

[61]  N. Dainiak Hematologic consequences of exposure to ionizing radiation. , 2002, Experimental hematology.

[62]  T. Pritts,et al.  Mucosal and enterocyte IL-6 production during sepsis and endotoxemia--role of transcription factors and regulation by the stress response. , 2002, American journal of surgery.

[63]  H. Knüpfer,et al.  sIL‐6R: more than an agonist? , 2008, Immunology and cell biology.

[64]  M. Hashizume,et al.  Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorates joint swelling in established monkey collagen-induced arthritis. , 2008, Biological and Pharmaceutical Bulletin.

[65]  S. Akira,et al.  Toll-like receptors on hematopoietic progenitor cells stimulate innate immune system replenishment. , 2006, Immunity.

[66]  S. Akira,et al.  A nuclear factor for interleukin-6 expression (NF-IL6) and the glucocorticoid receptor synergistically activate transcription of the rat alpha 1-acid glycoprotein gene via direct protein-protein interaction , 1993, Molecular and cellular biology.

[67]  S. Tsai,et al.  IL-3 Induces Inhibitor of DNA-Binding Protein-1 in Hemopoietic Progenitor Cells and Promotes Myeloid Cell Development1 , 2005, The Journal of Immunology.

[68]  E. Deitch,et al.  Endotoxemia down‐regulates bone marrow lymphopoiesis but stimulates myelopoiesis: the effect of G6PD deficiency , 2008, Journal of leukocyte biology.

[69]  N. Mukaida,et al.  Essential involvement of IL‐6 in the skin wound‐healing process as evidenced by delayed wound healing in IL‐6‐deficient mice , 2003, Journal of leukocyte biology.

[70]  D. Scadden,et al.  Tumor necrosis factor-alpha and endothelial cells modulate Notch signaling in the bone marrow microenvironment during inflammation. , 2008, Experimental hematology.