title: Inhibition of p70(S6) kinase during transforming growth factor-beta 1/vitamin D(3)-induced monocyte differentiation of HL-60 cells allows tumor necrosis factor-alpha to stimulate plasminogen activator inhibitor-1 synthesis.
abstract: We investigated intracellular mechanisms involved in the up-regulation of plasminogen activator inhibitor I (PAI-1) synthesis by human recombinant tumor necrosis factor-alpha (TNF) during monocyte differentiation of HL-60 cells triggered by the transforming growth factor-beta1/vitamin D(3) (TGF/D3) mixture. TGF/D3-treated cells expressed surface monocytic markers and produced noticeable amounts of PAI-1 but stopped to proliferate. A reduced p70 S6 kinase (p70(S6K)) phosphorylation was also observed and, in this situation, TNF dramatically enhanced PAI-1 synthesis. Similarly, TNF significantly up-regulated PAI-1 synthesis when p70(S6K) phosphorylation was inhibited by rapamycin. This phenomenon was not due to a general decrease in protein synthesis but involved the activation of gene transcription rather than PAI-1 mRNA stabilization. The level of the transcriptional regulator factor E2F1, a repressor of PAI-1 gene expression, was shown to be down-modulated in TGF/D3- as well as in rapamycin-treated cells. Furthermore, the apoptotic effect of TNF in HL-60 cells appeared to be prevented by the addition of either TGF/D3 or rapamycin. In conclusion, these results indicate that inhibition of p70(S6K) phosphorylation during TGF/D3-induced monocyte differentiation of HL-60 cells is a determinant factor that allows TNF to exert its up-regulating effect on PAI-1 synthesis while protecting cells from apoptosis.
authors.affiliation: EPI 99-36, Laboratoire d'Hématologie, Faculté de Médecine, 27, Bd. Jean Moulin, Marseilles 13385 cedex 5, France. Franck.Peiretti@medecine.univ-mrs.fr
authors.forename: F
authors.initials: F
authors.lastname: Peiretti
authors.forename: S
authors.initials: S
authors.lastname: Lopez
authors.forename: P
authors.initials: P
authors.lastname: Deprez-Beauclair
authors.forename: B
authors.initials: B
authors.lastname: Bonardo
authors.forename: I
authors.initials: I
authors.lastname: Juhan-Vague
authors.forename: G
authors.initials: G
authors.lastname: Nalbone
mesh_terms: D018797:Cell Cycle Proteins; D002454:Cell Differentiation / Q000187:drug effects*; D002762:Cholecalciferol / Q000494:pharmacology*; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D017395:Plasminogen Activator Inhibitor 1; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D002762:Cholecalciferol; D019893:Ribosomal Protein S6 Kinases