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Extramedullary expansion of hematopoietic progenitor cells in interleukin (IL)-6-sIL-6R double transgenic mice.

Peters M, Schirmacher P, Goldschmitt J, Odenthal M, Peschel C, Fattori E, Ciliberto G, Dienes HP, Meyer zum Büschenfelde KH, Rose-John S - J. Exp. Med. (1997)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: I. Department of Medicine, University of Mainz, Germany.

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.

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Immunohistochemical  analysis of the Ly-6 (A–C), and  Ia (A′–C′) surface protein expression on hematopoietic liver  cells in IL-6–sIL-6R double-transgenic mice. Granulocytic (A) and  monocytic/macrophage (A′) cells  are almost completely absent in  the liver at the age of 4 wk. At 6  wk, scattered granulocytic (B)  and small clusters of monocytic/ macrophage cells (B′) appear in  the liver, representing early hepatic extramedullary hematopoiesis. At the age of 12 wk, there are  large confluent hepatic foci showing predominantly granulopoietic differentiation (C), but also  significant monopoietic cells (C′).  The scale bars indicate 100 μm.
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Figure 4: Immunohistochemical analysis of the Ly-6 (A–C), and Ia (A′–C′) surface protein expression on hematopoietic liver cells in IL-6–sIL-6R double-transgenic mice. Granulocytic (A) and monocytic/macrophage (A′) cells are almost completely absent in the liver at the age of 4 wk. At 6 wk, scattered granulocytic (B) and small clusters of monocytic/ macrophage cells (B′) appear in the liver, representing early hepatic extramedullary hematopoiesis. At the age of 12 wk, there are large confluent hepatic foci showing predominantly granulopoietic differentiation (C), but also significant monopoietic cells (C′). The scale bars indicate 100 μm.

Mentions: To characterize further the nature of the hematopoietic cells in the liver, immunohistochemistry was performed with antibodies to surface antigens of neutrophils (Ly-6), monocytes/macrophages (Ia), B cells (B220), and T cells (CD3). As early as 4 wk after birth, IL-6– sIL-6R mice showed single positive neutrophils (Fig. 4 A) and monocytes/macrophages (Fig. 4 A′) in the liver. At the age of 6 wk, there were increased numbers of scattered neutrophilic granulocytes (Fig. 4 B) and small clusters of monocytic cells (Fig. 4 B′) present in the liver. Large confluent foci of both cell types were detected at the age of 16 wk (Figs. 4, C and C′). Immunohistochemistry using antibodies directed against B and T cell epitopes revealed that B cells were also present, but to a lesser extent, and that T cells were absent (data not shown). In single-transgenic and nontransgenic littermates, immunohistochemistry using the above mentioned antibodies gave negative results (data not shown).


Extramedullary expansion of hematopoietic progenitor cells in interleukin (IL)-6-sIL-6R double transgenic mice.

Peters M, Schirmacher P, Goldschmitt J, Odenthal M, Peschel C, Fattori E, Ciliberto G, Dienes HP, Meyer zum Büschenfelde KH, Rose-John S - J. Exp. Med. (1997)

Immunohistochemical  analysis of the Ly-6 (A–C), and  Ia (A′–C′) surface protein expression on hematopoietic liver  cells in IL-6–sIL-6R double-transgenic mice. Granulocytic (A) and  monocytic/macrophage (A′) cells  are almost completely absent in  the liver at the age of 4 wk. At 6  wk, scattered granulocytic (B)  and small clusters of monocytic/ macrophage cells (B′) appear in  the liver, representing early hepatic extramedullary hematopoiesis. At the age of 12 wk, there are  large confluent hepatic foci showing predominantly granulopoietic differentiation (C), but also  significant monopoietic cells (C′).  The scale bars indicate 100 μm.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196150&req=5

Figure 4: Immunohistochemical analysis of the Ly-6 (A–C), and Ia (A′–C′) surface protein expression on hematopoietic liver cells in IL-6–sIL-6R double-transgenic mice. Granulocytic (A) and monocytic/macrophage (A′) cells are almost completely absent in the liver at the age of 4 wk. At 6 wk, scattered granulocytic (B) and small clusters of monocytic/ macrophage cells (B′) appear in the liver, representing early hepatic extramedullary hematopoiesis. At the age of 12 wk, there are large confluent hepatic foci showing predominantly granulopoietic differentiation (C), but also significant monopoietic cells (C′). The scale bars indicate 100 μm.
Mentions: To characterize further the nature of the hematopoietic cells in the liver, immunohistochemistry was performed with antibodies to surface antigens of neutrophils (Ly-6), monocytes/macrophages (Ia), B cells (B220), and T cells (CD3). As early as 4 wk after birth, IL-6– sIL-6R mice showed single positive neutrophils (Fig. 4 A) and monocytes/macrophages (Fig. 4 A′) in the liver. At the age of 6 wk, there were increased numbers of scattered neutrophilic granulocytes (Fig. 4 B) and small clusters of monocytic cells (Fig. 4 B′) present in the liver. Large confluent foci of both cell types were detected at the age of 16 wk (Figs. 4, C and C′). Immunohistochemistry using antibodies directed against B and T cell epitopes revealed that B cells were also present, but to a lesser extent, and that T cells were absent (data not shown). In single-transgenic and nontransgenic littermates, immunohistochemistry using the above mentioned antibodies gave negative results (data not shown).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: I. Department of Medicine, University of Mainz, Germany.

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.

Show MeSH