by Malte Peters, Albrecht M. Müller, and Stefan Rose-John

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by Malte Peters, Albrecht M. Müller, and Stefan Rose-John Interleukin-6 and Soluble Interleukin-6 Receptor: Direct Stimulation of gp130 and Hematopoiesis by Malte Peters, Albrecht M. Müller, and Stefan Rose-John Blood Volume 92(10):3495-3504 November 15, 1998 ©1998 by American Society of Hematology

Transsignaling of soluble receptors of IL-6 family. Transsignaling of soluble receptors of IL-6 family. An IL-6R–expressing cell (left) releases a soluble receptor by shedding or alternative splicing. This soluble receptor binds IL-6 and induces homodimerization of gp130 on a target cell (right) that expresses gp130 but no IL-6R. In this model, the target cell in the absence of soluble IL-6R is not responsive to IL-6. gp130, red; IL-6R black; IL-6, blue. This transsignaling model holds also true for the IL-6 family cytokines IL-11 and CNTF. Malte Peters et al. Blood 1998;92:3495-3504 ©1998 by American Society of Hematology

Malte Peters et al. Blood 1998;92:3495-3504 ©1998 by American Society of Hematology

Malte Peters et al. Blood 1998;92:3495-3504 ©1998 by American Society of Hematology

Target cells of IL-6 and the IL-6/soluble IL-6R complex. Target cells of IL-6 and the IL-6/soluble IL-6R complex. (A) Cells that express gp130 (gray) and membrane bound IL-6R (black) are responsive to IL-6 and are sensitized by the presence of the soluble IL-6R. (B) Cells that only express gp130 but no membrane bound IL-6R are unresponsive to IL-6 but can be stimulated by the complex of IL-6 and soluble IL-6R. Malte Peters et al. Blood 1998;92:3495-3504 ©1998 by American Society of Hematology

Frequency of cells with a hematopoietic stem cell phenotype in control, IL-6, or IL-6/soluble IL-6R transgenic mice. Frequency of cells with a hematopoietic stem cell phenotype in control, IL-6, or IL-6/soluble IL-6R transgenic mice. The presence of Lin−/Sca1+/c-kit+cells present in bone marrow, spleen, and liver of (□) control mice, (▨) IL-6 transgenic mice, and (▪) IL-6/soluble IL-6R double-transgenic mice was analyzed by FACS. Malte Peters et al. Blood 1998;92:3495-3504 ©1998 by American Society of Hematology

Peripheral blood cells of control, IL-6, or IL-6/soluble IL-6R transgenic mice. Peripheral blood cells of control, IL-6, or IL-6/soluble IL-6R transgenic mice. White blood cell (A), neutrophil (B), platelets (C), red blood cells (D), and hemoglobin (E) values were analyzed from six transgenic mice and nontransgenic littermates per group at the ages indicated. Mean values with standard deviations are presented. Malte Peters et al. Blood 1998;92:3495-3504 ©1998 by American Society of Hematology

Expansion of CD34+ human cord blood-derived progenitor cells in the presence of IL-6 or IL-6/soluble IL-6R. Expansion of CD34+ human cord blood-derived progenitor cells in the presence of IL-6 or IL-6/soluble IL-6R. Two thousand CD34+ cord blood cells containing 684 progenitors were cultured in serum containing suspension culture medium supplemented with the factors indicated. The expansion of hematopoietic progenitor cells was tested after 2 weeks of liquid culture in methylcellulose assays. Adapted and reprinted with permission from Sui et al.54 Copyright 1995 National Academy of Sciences, U.S.A. Malte Peters et al. Blood 1998;92:3495-3504 ©1998 by American Society of Hematology

Hyper-IL-6: a highly active designer cytokine consisting of IL-6 and soluble IL-6R. Hyper-IL-6: a highly active designer cytokine consisting of IL-6 and soluble IL-6R. Molecular model of the fusion protein consisting of IL-6 (gray) and sIL-6R (yellow) fused by a flexible peptide linker (green). A, B, C, and D denote the four helices of IL-6; D-II and D-III are the two cytokine-binding receptor domains of the sIL-6R used for the construction of the fusion protein. Malte Peters et al. Blood 1998;92:3495-3504 ©1998 by American Society of Hematology

gp130 stimulation via soluble or membrane-bound IL-6R. gp130 stimulation via soluble or membrane-bound IL-6R. (A) A donor cell (bottom) releases the soluble IL-6R that, in the presence of IL-6, stimulates the target cell (top) to dimerize gp130 (gray) and initiate signal transduction. (B) The contact between donor cell (bottom) and target cell (top) is mediated by the membrane-bound IL-6R of the donor cell, IL-6, and the two gp130 molecules of the target cell leading to gp130 dimerization and signaling. For reasons of simplicity, on donor cells, gp130 has been omitted. Malte Peters et al. Blood 1998;92:3495-3504 ©1998 by American Society of Hematology

Cellular responsiveness to IL-6 or IL-6/soluble IL-6R is determined by the expression levels of IL-6R. Cellular responsiveness to IL-6 or IL-6/soluble IL-6R is determined by the expression levels of IL-6R. The number of the ubiquitously expressed gp130 protein (red) is believed to be rather constant on all cells of the organism. The number of the IL-6R molecules (black) varies on different cell types. See text for explanations. Malte Peters et al. Blood 1998;92:3495-3504 ©1998 by American Society of Hematology