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Analysis of the synergistic stimulation of mouse macrophage proliferation by macrophage colony‐stimulating factor (CSF‐1) and tumor necrosis factor a (TNF‐α)
Author(s) -
Guilbert Larry J.,
WinklerLowen Bonnie,
Smith Anne,
Branch Donald R.,
GarciaLloret Maria
Publication year - 1993
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1002/jlb.54.1.65
Subject(s) - macrophage colony stimulating factor , tumor necrosis factor alpha , macrophage , biology , granulocyte macrophage colony stimulating factor , cell growth , colony stimulating factor , thymidine , cell culture , growth factor , stimulation , cytokine , dna synthesis , medicine , necrosis , endocrinology , microbiology and biotechnology , immunology , in vitro , receptor , biochemistry , stem cell , genetics , haematopoiesis
Tumor necrosis factor a (TNF‐α) more than doubles tritiated thymidine ([3H]TdR) uptake in mouse macrophages stimulated by macrophage colony‐ stimulating factor (CSF‐1). However, nothing is known of how TNF‐α affects this increase or even whether it is manifested by increased cellular proliferation. Here we characterize the effects of TNF‐α on CSF‐l‐stimulated proliferation of both primary cells (bone marrow‐derived macrophages, BMMs) and a cloned growth factor‐dependent macrophage cell line (SI). We show that the TNF‐ α‐induced increase in [3H]TdR uptake of CSF‐l‐stimu‐ lated macrophages is directly proportional to an increase in the DNA content of the culture and that the effects of TNF‐α are direct and independent of cell number. TNF‐a decreases the population doubling time of log‐phase growing macrophages having quite different growth rates to the same (approximately 30%) extent: the doubling time of BMMs decreases from 24 to 17 h and that of SI cells from 17 to 13 h. TNF‐α exerts its effects on log‐phase growth by increasing to the same proportion CSF‐l‐stimulated proliferation at all concentrations of CSF‐1; that is, TNF‐α does not shift, but rather amplifies, the CSF‐1 dose‐response curve. Although TNF‐α alone does not stimulate macrophage proliferation, its presence in S1 cell cultures coming to quiescence after withdrawal of CSF‐1 greatly increases subsequent CSF‐l‐stimulated [3H]TdR uptake as the cells reenter the cycle. Finally, we show that both human and mouse TNF‐α increase CSF‐l‐stimulated log‐phase growth and reentry of quiescent cells into the cycle equally on a molar basis (halfmaximal stimulation of approximately 0.3 nM). The latter observation argues that the growth‐stimulatory effects of TNF‐α are mediated via the 55‐60‐kd TNF receptor. We conclude that TNF‐α acts directly on growth‐ competent macrophages to decrease significantly the population doubling time in a manner that enhances the mitogenic effects of CSF‐1.