TNF-α inhibits the further development of committed progenitors while stimulating multipotential progenitors in mouse long-term bone marrow cultures

Jim A Rogers, Joan W. Berman

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

We studied simultaneously the effect of TNF on both relatively primitive and more mature hematopoietic progenitors by using a modification of the mouse long-term bone marrow culture system of Dexter. Mycophenolic acid- treated long-term bone marrow cultures were charged with stromally depleted bone marrow cells along with 10 to 500 U/ml recombinant human TNF-α, and assayed each week for 5 wk for the presence of primitive (CFU-S and high proliferative potential colony-forming cell) and mature (CFU-C) colony- forming units. The results demonstrate that TNF-α has differential effects on hematopoiesis; it virtually eliminates CFU-C, significantly lowers high proliferative potential colony-forming cell (CFC) numbers and increases CFU- S numbers. This effect appears to be independent of CSF production in the cultures as shown by protein assays. Northern blot analyses showed no differences in expression of CSF genes or any expression of those encoding for IL-1, IL-3, or IL-6. These results, obtained in a long-term culture system that closely mimics in vivo bone marrow, demonstrate that many of the apparently contradictory effects of TNF observed in vitro occur concomitantly and are attributable to the presence of cells at various stages of maturity in the cultures. The data suggest a mechanism of this activity in which TNF is able to block the differentiation of primitive progenitors even as they are stimulated to proliferate.

Original languageEnglish (US)
Pages (from-to)4694-4703
Number of pages10
JournalJournal of Immunology
Volume153
Issue number10
StatePublished - Nov 15 1994

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Bone Marrow
Mycophenolic Acid
Interleukin-3
Hematopoiesis
Interleukin-1
Bone Marrow Cells
Northern Blotting
Interleukin-6
Stem Cells
Cell Count
Gene Expression
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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abstract = "We studied simultaneously the effect of TNF on both relatively primitive and more mature hematopoietic progenitors by using a modification of the mouse long-term bone marrow culture system of Dexter. Mycophenolic acid- treated long-term bone marrow cultures were charged with stromally depleted bone marrow cells along with 10 to 500 U/ml recombinant human TNF-α, and assayed each week for 5 wk for the presence of primitive (CFU-S and high proliferative potential colony-forming cell) and mature (CFU-C) colony- forming units. The results demonstrate that TNF-α has differential effects on hematopoiesis; it virtually eliminates CFU-C, significantly lowers high proliferative potential colony-forming cell (CFC) numbers and increases CFU- S numbers. This effect appears to be independent of CSF production in the cultures as shown by protein assays. Northern blot analyses showed no differences in expression of CSF genes or any expression of those encoding for IL-1, IL-3, or IL-6. These results, obtained in a long-term culture system that closely mimics in vivo bone marrow, demonstrate that many of the apparently contradictory effects of TNF observed in vitro occur concomitantly and are attributable to the presence of cells at various stages of maturity in the cultures. The data suggest a mechanism of this activity in which TNF is able to block the differentiation of primitive progenitors even as they are stimulated to proliferate.",
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AB - We studied simultaneously the effect of TNF on both relatively primitive and more mature hematopoietic progenitors by using a modification of the mouse long-term bone marrow culture system of Dexter. Mycophenolic acid- treated long-term bone marrow cultures were charged with stromally depleted bone marrow cells along with 10 to 500 U/ml recombinant human TNF-α, and assayed each week for 5 wk for the presence of primitive (CFU-S and high proliferative potential colony-forming cell) and mature (CFU-C) colony- forming units. The results demonstrate that TNF-α has differential effects on hematopoiesis; it virtually eliminates CFU-C, significantly lowers high proliferative potential colony-forming cell (CFC) numbers and increases CFU- S numbers. This effect appears to be independent of CSF production in the cultures as shown by protein assays. Northern blot analyses showed no differences in expression of CSF genes or any expression of those encoding for IL-1, IL-3, or IL-6. These results, obtained in a long-term culture system that closely mimics in vivo bone marrow, demonstrate that many of the apparently contradictory effects of TNF observed in vitro occur concomitantly and are attributable to the presence of cells at various stages of maturity in the cultures. The data suggest a mechanism of this activity in which TNF is able to block the differentiation of primitive progenitors even as they are stimulated to proliferate.

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