Transforming growth factor-β1 is an autocrine mediator of U937 cell growth arrest and differentiation induced by vitamin D3 and retinoids
✍ Scribed by Hélène Defacque; David Piquemal; Annie Basset; Jacques Marti; Thérèse Commes
- Publisher
- John Wiley and Sons
- Year
- 1999
- Tongue
- English
- Weight
- 336 KB
- Volume
- 178
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Vitamin D and retinoids cooperate to inhibit the proliferation and induce the differentiation of human myelomonocytic U937 leukemia cells. In the present work, we investigated the role of TGF- as an endogenous mediator of this process. We found that the TGF-1 precursor began to accumulate in cell culture supernatants soon after the addition of 1␣,25 dihydroxyvitamin D 3 (VD) and retinoids. We used neutralizing antibodies (AbTGF-) and antisense oligonucleotide (AS Oligo) to inhibit its possible effects. Our data demonstrated that AbTGF- partially inhibit the expression of the differentiated phenotype, as assessed by measurement of phagocytic activity, response to the chemotactic peptide fMLP, and lysozyme secretion. AS Oligo was also inhibitory, and the effects of AS Oligo and AbTGF- were cumulative. Cell growth inhibition induced by VD and retinoids was completely reversed, and differentiation was reduced by about 75% when both inhibitors were associated. Time course experiments based on the delayed addition of AbTGF- and AS Oligo showed that TGF-1 was required for cell differentiation 24 h after the addition of inducers. Studies on TGF- receptors revealed that, while the expression of type II receptor was stable, the level of type I TGF- receptor mRNA and the expression of the protein began to decline early during the differentiation process. As a whole, these results support the notion that an autocrine TGF- pathway, activated by VD and retinoids in U937 cells, is involved in the early steps of the process leading to cell growth arrest and differentiation.