Modulation of PAI-1 and proMMP-9 syntheses by soluble TNFα and its receptors during differentiation of the human monocytic HL-60 cell line
✍ Scribed by Franck Peiretti; Denis Bernot; Sophie Lopez; Bernadette Bonardo; Paule Deprez-Beauclair; Irène Juhan-Vague; Gilles Nalbone
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- English
- Weight
- 196 KB
- Volume
- 196
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
During phorbol ester‐induced differentiation of HL‐60 monocytic cells, tumor necrosis factorα (TNFα) synthesis and secretion are increased, which contributes to the autocrine regulation of TNFα‐responsive genes. We investigated how, during phorbol ester‐induced differentiation of HL‐60 cells, the secreted TNFα modulated plasminogen activator inhibitor type I (PAI‐1) and gelatinase B (MMP‐9) syntheses, two proteins involved in pericellular proteolysis. The differentiation‐induced release of TNFα, was abolished by the hydroxamate‐based matrix metalloproteinase (MMP) inhibitor, RU36156. RU36156 or a neutralizing anti‐TNFα significantly down‐regulated PAI‐1 synthesis exclusively during the early phases of differentiation (from promyelocyte to monocytic‐like cells), which underlined the activating role of autocrine TNFα during this time range. As cells progressed to monocyte/macrophage phenotype, they still released TNFα, but RU36156 or anti‐TNFα no longer had an effect on PAI‐1 synthesis. This lack of effect was not due to a default of TNFα signaling since PAI‐1 synthesis was still stimulated in response to exogenous TNFα. TNFα receptor RI was also actively released and was shown to reduce TNFα activity which may account for the inability of soluble TNFα to up‐regulate PAI‐1 synthesis. In later mature stage, cells became susceptible to exogenous TNFα‐induced apoptosis and rapidly lost their ability to respond to TNFα. The MMP‐9 synthesis followed similar regulation as PAI‐1. Isolated human blood monocytes‐derived macrophages behave like HL‐60‐derived macrophages. In conclusion, these results show that during leukocyte differentiation, time windows exist during which the autocrine TNFα is active and then down‐regulated by RI, which may temper a continuous up‐regulation of the synthesis of proteins involved in pericellular proteolysis. J. Cell. Physiol. 196: 346–353, 2003. © 2003 Wiley‐Liss, Inc.