Previous experiments have revealed the expression of tumor necrosis factor α (TNF-α) transcripts in all murine bone marrow-derived macrophage colonies isolated from days 5 through 9 of differentiation in vitro. These results implicated a role for TNF-α gene expression during macrophage differentiation. Antisense oligomers to the initiation region of the TNF-α message were used to inhibit its expression, thus allowing the role of TNF-α gene expression in controlling the differentiation of macrophages to be determined. Results showed that TNF-α regulated the proliferation of macrophages during differentiation. Cells isolated on day 3 were exclusively vulnerable to the effects of blocking TNF-α gene expression, displaying a 30% increase in proliferation over control cells or sense oligomer-treated cells. Thus, in the absence of TNF-α gene expression, cells maintained proliferation instead of undergoing terminal differentiation. Exogenous TNF-α was capable of rescuing day 3 antisense-treated cells, therefore maintaining normal levels of proliferation. In contrast, blocking interleukin 1β gene expression by antisense oligonucleotide treatment had no effect on proliferation. Addition of exogenous recombinant murine or human TNF-α decreased the total cell number 25-50% regardless of whether cells were grown in medium containing colony-stimulating factor 1 (CSF-1) or granulocyte-macrophage colony-stimulating factor (GM-CSF). These results suggested that exogenous TNF-α suppressed proliferation of early hematopoietic progenitors, whereas endogenous TNF-α regulated proliferation of macrophage progenitors. The number of differentiated, adherent macrophages on day 5 of differentiation in vitro was increased by TNF-α treatment of GM-CSF-induced macrophages but was suppressed in CSF-1-induced macrophages. These findings suggest that distinct TNF receptor expression and/or signaling is induced in differentiating macrophages stimulated with either growth factor.

Original languageEnglish (US)
Pages (from-to)4754-4758
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number10
StatePublished - Jan 1 1992


  • Cytokines
  • Hematopoiesis
  • Macrophage growth factors
  • Macrophage heterogeneity

ASJC Scopus subject areas

  • Genetics
  • General

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