Prostaglandin E2 induced the differentiation of osteoclasts in mouse osteoblast-depleted bone marrow cells

Intravenous (IV) injection of 0.1 to 10 micrograms of authentic prostaglandin E2 (PGE2) in intact steady-state mice induces a population of bone marrow and spleen cells having the capacity to suppress CFU-GM proliferation when admixed with normal bone marrow cells. Equivalent suppression of CFU-GM committed to monocytic as well as granulocytic differentiation was observed using colony-stimulating factors (CSFs) differing in their lineage specificities and by direct morphological analysis of proliferating clones. Kinetic analysis indicates that suppressive bone marrow cells appear within 2 hours after PGE2 injection, are maximal at 6 hours, and are no longer observed by 24 hours postinjection. Positive and negative selection studies using monoclonal antibodies indicate that the PGE2-induced suppressor cells react positively with anti-GMA 1.2, MAC1, and F4/80 monoclonal antibodies, suggesting a myeloid/monocytic origin. As few as 1,000 positively selected bone marrow or spleen cells were able to inhibit maximally normal CFU-GM proliferation by 50,000 control bone marrow cells. Suppression of normal CFU-GM can be substituted for by 24- hour cell-free supernates from unseparated bone marrow cells or GMA 1.2 or F4/80 positively selected marrow or spleen cells from PGE2-treated but not control mice. These supernates also inhibited BFU-E proliferation. Injection of as few as 2 million bone marrow cells from PGE2-treated mice into steady-state mice or animals hematopoietically rebounding following a sublethal injection of cyclophosphamide significantly suppressed total CFU-GM proliferation in recipient mice within 6 hours. In summary, these studies describe the detection of a novel hematopoietic control network induced by PGE2 in intact mice.

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In vivo modulation of myelopoiesis by prostaglandin E2. III. Induction of suppressor cells in marrow and spleen capable of mediating inhibition of CFU-GM proliferation

Blood ◽

10.1182/blood.v71.6.1633.1633 ◽

1988 ◽

Vol 71 (6) ◽

pp. 1633-1640 ◽

Cited By ~ 18

Author(s):

LM Pelus ◽

PS Gentile

Keyword(s):

Bone Marrow ◽

Monoclonal Antibodies ◽

Steady State ◽

Prostaglandin E2 ◽

Bone Marrow Cells ◽

Suppressor Cells ◽

Spleen Cells ◽

Granulocytic Differentiation ◽

Marrow Cells

Abstract Intravenous (IV) injection of 0.1 to 10 micrograms of authentic prostaglandin E2 (PGE2) in intact steady-state mice induces a population of bone marrow and spleen cells having the capacity to suppress CFU-GM proliferation when admixed with normal bone marrow cells. Equivalent suppression of CFU-GM committed to monocytic as well as granulocytic differentiation was observed using colony-stimulating factors (CSFs) differing in their lineage specificities and by direct morphological analysis of proliferating clones. Kinetic analysis indicates that suppressive bone marrow cells appear within 2 hours after PGE2 injection, are maximal at 6 hours, and are no longer observed by 24 hours postinjection. Positive and negative selection studies using monoclonal antibodies indicate that the PGE2-induced suppressor cells react positively with anti-GMA 1.2, MAC1, and F4/80 monoclonal antibodies, suggesting a myeloid/monocytic origin. As few as 1,000 positively selected bone marrow or spleen cells were able to inhibit maximally normal CFU-GM proliferation by 50,000 control bone marrow cells. Suppression of normal CFU-GM can be substituted for by 24- hour cell-free supernates from unseparated bone marrow cells or GMA 1.2 or F4/80 positively selected marrow or spleen cells from PGE2-treated but not control mice. These supernates also inhibited BFU-E proliferation. Injection of as few as 2 million bone marrow cells from PGE2-treated mice into steady-state mice or animals hematopoietically rebounding following a sublethal injection of cyclophosphamide significantly suppressed total CFU-GM proliferation in recipient mice within 6 hours. In summary, these studies describe the detection of a novel hematopoietic control network induced by PGE2 in intact mice.

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Prostaglandin E2 restrains macrophage maturation via E prostanoid receptor 2/protein kinase A signaling

Blood ◽

10.1182/blood-2011-08-374207 ◽

2012 ◽

Vol 119 (10) ◽

pp. 2358-2367 ◽

Cited By ~ 40

Author(s):

Zbigniew Zasłona ◽

Carlos H. Serezani ◽

Katsuhide Okunishi ◽

David M. Aronoff ◽

Marc Peters-Golden

Keyword(s):

Bone Marrow ◽

Protein Kinase ◽

Prostaglandin E2 ◽

Protein Kinase A ◽

Bone Marrow Cells ◽

Lipid Mediator ◽

Wild Type ◽

Kinase A ◽

Marrow Cells

Abstract Prostaglandin E2 (PGE2) is a lipid mediator that acts by ligating 4 distinct G protein–coupled receptors, E prostanoid (EP) 1 to 4. Previous studies identified the importance of PGE2 in regulating macrophage functions, but little is known about its effect on macrophage maturation. Macrophage maturation was studied in vitro in bone marrow cell cultures, and in vivo in a model of peritonitis. EP2 was the most abundant PGE2 receptor expressed by bone marrow cells, and its expression further increased during macrophage maturation. EP2-deficient (EP2−/−) macrophages exhibited enhanced in vitro maturation compared with wild-type cells, as evidenced by higher F4/80 expression. An EP2 antagonist also increased maturation. In the peritonitis model, EP2−/− mice exhibited a higher percentage of F4/80high/CD11bhigh cells and greater expression of macrophage colony-stimulating factor receptor (M-CSFR) in both the blood and the peritoneal cavity. Subcutaneous injection of the PGE2 analog misoprostol decreased M-CSFR expression in bone marrow cells and reduced the number of peritoneal macrophages in wild-type mice but not EP2−/− mice. The suppressive effect of EP2 ligation on in vitro macrophage maturation was mimicked by a selective protein kinase A agonist. Our findings reveal a novel role for PGE2/EP2/protein kinase A signaling in the suppression of macrophage maturation.

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Effects of prostaglandin E2 on the micronucleus formation in mouse bone marrow cells by various mutagens

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/0027-5107(94)90187-2 ◽

1994 ◽

Vol 311 (2) ◽

pp. 287-293 ◽

Cited By ~ 9

Author(s):

Yuji Suzuki ◽

Hidesuke Shimizu ◽

Tomoharu Ishikawa ◽

Hideyuki Sakaba ◽

Masakatsu Fukumoto ◽

...

Keyword(s):

Bone Marrow ◽

Prostaglandin E2 ◽

Bone Marrow Cells ◽

Mouse Bone Marrow ◽

Micronucleus Formation ◽

Mouse Bone Marrow Cells ◽

Marrow Cells

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In vivo prostaglandin E2 treatment alters the bone marrow microenvironment and preferentially expands short-term hematopoietic stem cells

Blood ◽

10.1182/blood-2009-03-205823 ◽

2009 ◽

Vol 114 (19) ◽

pp. 4054-4063 ◽

Cited By ~ 58

Author(s):

Benjamin J. Frisch ◽

Rebecca L. Porter ◽

Benjamin J. Gigliotti ◽

Adam J. Olm-Shipman ◽

Jonathan M. Weber ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Prostaglandin E2 ◽

Bone Marrow Cells ◽

Negative Impact ◽

Hematopoietic Progenitors ◽

Short Term ◽

Hematopoietic Stem ◽

Marrow Cells

Abstract Microenvironmental signals can determine hematopoietic stem cell (HSC) fate choices both directly and through stimulation of niche cells. In the bone marrow, prostaglandin E2 (PGE2) is known to affect both osteoblasts and osteoclasts, whereas in vitro it expands HSCs and affects differentiation of hematopoietic progenitors. We hypothesized that in vivo PGE2 treatment could expand HSCs through effects on both HSCs and their microenvironment. PGE2-treated mice had significantly decreased number of bone trabeculae, suggesting disruption of their microarchitecture. In addition, in vivo PGE2 increased lineage− Sca-1+ c-kit+ bone marrow cells without inhibiting their differentiation. However, detailed immunophenotyping demonstrated a PGE2-dependent increase in short-term HSCs/multipotent progenitors (ST-HSCs/MPPs) only. Bone marrow cells transplanted from PGE2 versus vehicle-treated donors had superior lymphomyeloid reconstitution, which ceased by 16 weeks, also suggesting that ST-HSCs were preferentially expanded. This was confirmed by serial transplantation studies. Thus in vivo PGE2 treatment, probably through a combination of direct and microenvironmental actions, preferentially expands ST-HSCs in the absence of marrow injury, with no negative impact on hematopoietic progenitors or long-term HSCs. These novel effects of PGE2 could be exploited clinically to increase donor ST-HSCs, which are highly proliferative and could accelerate hematopoietic recovery after stem cell transplantation.

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