Extramedullary Expansion of Hematopoietic Progenitor Cells in Interleukin (IL)-6–sIL-6R Double Transgenic Mice

Abstract

Soluble cytokine receptors modulate the activity of their cognate ligands. Interleukin (IL)-6 in association with the soluble IL-6 receptor (sIL-6R) can activate cells expressing the gp130 signal transducer lacking the specific IL-6R. To investigate the function of the IL-6–sIL-6R complex in vivo and to discriminate the function of the IL-6–sIL-6R complex from the function of IL-6 alone, we have established a transgenic mouse model. Double-transgenic mice coexpressing IL-6 and sIL-6R were generated and compared with IL-6 and sIL-6R single-transgenic mice. The main phenotype found in IL-6–sIL-6R mice was a dramatic increase of extramedullary hematopoietic progenitor cells in liver and spleen but not in the bone marrow. In IL-6 single-transgenic mice and sIL-6R single-transgenic mice no such effects were observed. The high numbers of hematopoietic progenitor cells were reflected by a strong increase of peripheral blood cell numbers. Therefore, activators of the gp130 signal transducer like the IL-6–IL-6R complex may represent most powerful stimulators for extramedullary hematopoietic progenitor cells. gp130 activators may become important for the expansion of hematopoietic progenitor cells in vivo and in vitro.

Gp130-Signaling synergizes with FL and TPO for the long-term expansion of cord blood progenitors

“…47 Evidence that IL-6 complexed to the soluble IL-6R, but not IL-6 alone, may be able to stimulate early murine progenitors, comes from phenotypic analyses of mice single transgenic for either IL-6 or sIL-6R or double transgenic for both IL-6 and sIL-6R. 34,39,40 Interestingly, double transgenic mice developed a marked extramedullary hematopoiesis in the spleen and to a lesser extent the liver while the bone marrow cellularity was not significantly changed. The liver showed distinct foci with predominantly granulopoietic cells, while large numbers of erythrocytes, granulocytes and megakaryocytes were found equally distributed in the spleen.…”

“…It has been hypothesized that the IL-6/sIL-6R complex is able to expand primitive resident stem cells in these primary hematopoietic organs in vivo. 34,39,40 An important objective of the present study was to investigate the potential benefit of the new designer recombinant IL-6 and sIL-6R fusion protein, H-IL-6, for the ex vivo expansion of hematopoietic UCB progenitors. Using stroma-free and stroma-supported long-term cultures, we compared several cytokine combinations in the presence or absence of this chimeric protein or with IL-6 and estimated the progenitor output by multiparameter FACS analyses and CAFC (cobblestone area forming cell) assays.…”

Interleukin-6 (IL-6) Induces Insulin Resistance in 3T3-L1 Adipocytes and Is, Like IL-8 and Tumor Necrosis Factor-α, Overexpressed in Human Fat Cells from Insulin-resistant Subjects

“…Double transgenic mice, overexpressing both sIL-6 receptor and IL-6, are smaller than their wild type littermates and have reduced body weight. These animals have markedly reduced fat depots, enlarged spleen, and shrunken disfigured livers, suggesting a role for IL-6 in cell growth (30). Furthermore, a recent study showed that mice completely lacking IL-6 became obese and that intracerobroventricular injection of IL-6 increased energy expenditure (31).…”

Abrogation of Viral Interleukin-6 (vIL-6)-Induced Signaling by Intracellular Retention and Neutralization of vIL-6 with an Anti-vIL-6 Single-Chain Antibody Selected by Phage Display

“…Furthermore, it was shown that the sIL-6-R strongly sensitizes IL-6-responsive target cells (59). transsignaling cell types that are exclusively responsive to IL-6/IL-6-R but not to IL-6 alone include hematopoietic progenitor cells (61), endothelial cells (67), osteoclasts (77), smooth muscle cells (32), and neuronal cells (39,40).…”