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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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Histomorphological analysis of livers and spleens in IL-6–sIL-6R  (A–D), and IL-6 (A′–D′) mice. (A)  Liver tissue with several hematopoietic  foci containing predominantly granulopoietic precursor cells and terminally  differentiated segmental granulocytes  (IL-6–sIL-6R, 8 wk). (A′) Normal liver  tissue with absence of hematopoietic  foci in an 8-wk-old IL-6 transgenic  mouse. (B) Spleen tissue with activated  extramedullary hematopoiesis showing  enlarged granulopoietic and erythropoietic areas as well as increased number of  megakaryocytes (IL-6–sIL-6R, 8 wk).  (B′) Spleen tissue from an IL-6 transgenic mouse at 8 wk showing regular  distribution of red and white pulp and  little hematopoiesis. (C) Liver tissue  with large hematopoietic focus displaying blastic precursor cells and terminally  differentiated granulocytes (IL-6–sIL6R, 16 wk). (C′) Liver tissue from an  IL-6 transgenic mouse at 16 wk with  periportal plasmacytoma infiltrate. (D)  Spleen tissue with destroyed architecture  and complete involvement by hematopoiesis (IL-6–sIL-6R, 16 wk). (D′)  Spleen tissue completely infiltrated by  plasmacytoma (IL-6, 16 wk). The scale  bars indicate 100 μm.
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Figure 3: Histomorphological analysis of livers and spleens in IL-6–sIL-6R (A–D), and IL-6 (A′–D′) mice. (A) Liver tissue with several hematopoietic foci containing predominantly granulopoietic precursor cells and terminally differentiated segmental granulocytes (IL-6–sIL-6R, 8 wk). (A′) Normal liver tissue with absence of hematopoietic foci in an 8-wk-old IL-6 transgenic mouse. (B) Spleen tissue with activated extramedullary hematopoiesis showing enlarged granulopoietic and erythropoietic areas as well as increased number of megakaryocytes (IL-6–sIL-6R, 8 wk). (B′) Spleen tissue from an IL-6 transgenic mouse at 8 wk showing regular distribution of red and white pulp and little hematopoiesis. (C) Liver tissue with large hematopoietic focus displaying blastic precursor cells and terminally differentiated granulocytes (IL-6–sIL6R, 16 wk). (C′) Liver tissue from an IL-6 transgenic mouse at 16 wk with periportal plasmacytoma infiltrate. (D) Spleen tissue with destroyed architecture and complete involvement by hematopoiesis (IL-6–sIL-6R, 16 wk). (D′) Spleen tissue completely infiltrated by plasmacytoma (IL-6, 16 wk). The scale bars indicate 100 μm.

Mentions: The increase of liver and spleen weight in IL-6–sIL-6R mice was caused by a marked extramedullary proliferation of hematopoietic cells in both organs (Fig. 3, A–D), which was not detected in any other parenchymal organ. No extramedullary hematopoiesis was found in single-transgenic and nontransgenic littermates (Fig. 3, A′–D′; data not shown). In the livers and spleens of IL-6–sIL-6R mice, multiple hematopoietic foci were present, which increased in size with time. At 8 wk, there were occasional foci (Figs. 3, A and B) present in both organs. However, at 16 wk, complete involvement of liver and spleen with multiple and large confluent hematopoietic foci accompanied by loss of the parenchymal organ architecture was demonstrated (Fig. 3, C and D). Determination of enzymatic values in the serum (LDH, alkaline phosphatase, and transaminases) did not show any alteration either in IL-6–sIL-6R mice or in single-transgenic and nontransgenic littermates (data not shown), indicating that the liver function of the mice was not compromised.


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)

Histomorphological analysis of livers and spleens in IL-6–sIL-6R  (A–D), and IL-6 (A′–D′) mice. (A)  Liver tissue with several hematopoietic  foci containing predominantly granulopoietic precursor cells and terminally  differentiated segmental granulocytes  (IL-6–sIL-6R, 8 wk). (A′) Normal liver  tissue with absence of hematopoietic  foci in an 8-wk-old IL-6 transgenic  mouse. (B) Spleen tissue with activated  extramedullary hematopoiesis showing  enlarged granulopoietic and erythropoietic areas as well as increased number of  megakaryocytes (IL-6–sIL-6R, 8 wk).  (B′) Spleen tissue from an IL-6 transgenic mouse at 8 wk showing regular  distribution of red and white pulp and  little hematopoiesis. (C) Liver tissue  with large hematopoietic focus displaying blastic precursor cells and terminally  differentiated granulocytes (IL-6–sIL6R, 16 wk). (C′) Liver tissue from an  IL-6 transgenic mouse at 16 wk with  periportal plasmacytoma infiltrate. (D)  Spleen tissue with destroyed architecture  and complete involvement by hematopoiesis (IL-6–sIL-6R, 16 wk). (D′)  Spleen tissue completely infiltrated by  plasmacytoma (IL-6, 16 wk). The scale  bars indicate 100 μm.
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Related In: Results  -  Collection

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Figure 3: Histomorphological analysis of livers and spleens in IL-6–sIL-6R (A–D), and IL-6 (A′–D′) mice. (A) Liver tissue with several hematopoietic foci containing predominantly granulopoietic precursor cells and terminally differentiated segmental granulocytes (IL-6–sIL-6R, 8 wk). (A′) Normal liver tissue with absence of hematopoietic foci in an 8-wk-old IL-6 transgenic mouse. (B) Spleen tissue with activated extramedullary hematopoiesis showing enlarged granulopoietic and erythropoietic areas as well as increased number of megakaryocytes (IL-6–sIL-6R, 8 wk). (B′) Spleen tissue from an IL-6 transgenic mouse at 8 wk showing regular distribution of red and white pulp and little hematopoiesis. (C) Liver tissue with large hematopoietic focus displaying blastic precursor cells and terminally differentiated granulocytes (IL-6–sIL6R, 16 wk). (C′) Liver tissue from an IL-6 transgenic mouse at 16 wk with periportal plasmacytoma infiltrate. (D) Spleen tissue with destroyed architecture and complete involvement by hematopoiesis (IL-6–sIL-6R, 16 wk). (D′) Spleen tissue completely infiltrated by plasmacytoma (IL-6, 16 wk). The scale bars indicate 100 μm.
Mentions: The increase of liver and spleen weight in IL-6–sIL-6R mice was caused by a marked extramedullary proliferation of hematopoietic cells in both organs (Fig. 3, A–D), which was not detected in any other parenchymal organ. No extramedullary hematopoiesis was found in single-transgenic and nontransgenic littermates (Fig. 3, A′–D′; data not shown). In the livers and spleens of IL-6–sIL-6R mice, multiple hematopoietic foci were present, which increased in size with time. At 8 wk, there were occasional foci (Figs. 3, A and B) present in both organs. However, at 16 wk, complete involvement of liver and spleen with multiple and large confluent hematopoietic foci accompanied by loss of the parenchymal organ architecture was demonstrated (Fig. 3, C and D). Determination of enzymatic values in the serum (LDH, alkaline phosphatase, and transaminases) did not show any alteration either in IL-6–sIL-6R mice or in single-transgenic and nontransgenic littermates (data not shown), indicating that the liver function of the mice was not compromised.

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
Related in: MedlinePlus