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Thromb Haemost 1999; 81(03): 415-422
DOI: 10.1055/s-0037-1614488
Review Article
Schattauer GmbH

Activation of Plasminogen Activator Inhibitor-1 Synthesis by Phorbol Esters in Human Promyelocyte HL-60

Roles of PKCß and MAPK p42
Sophie Lopez
,
Franck Peiretti
,
Pierre Morange
,
Amale Laouar
1   From Laboratoire d’Hématologie, Faculté de Médecine, Marseille, France; Center for Mechanistic Biology and Biotechnology, Argonne National Laboratory, Argonne, IL, USA
,
Chantal Fossat
,
Bernadette Bonardo
,
Eliezer Huberman
1   From Laboratoire d’Hématologie, Faculté de Médecine, Marseille, France; Center for Mechanistic Biology and Biotechnology, Argonne National Laboratory, Argonne, IL, USA
,
Irène Juhan-Vague
,
Gilles Nalbone
› Author AffiliationsThis work was supported by funds from INSERM and Ministère Enseignement Supérieure et de la Recherche. S. L. is a recipient of Sanofi-GEHT funding. The excellent technical assistance of M. Verdier (PAI-1 ELISA assays), V. Thomé (cell culture) and N. Fernandez (cytometry analyses) is acknowledged. The authors are indebted to Mrs M. Henry for her valuable advices for PCR analyses.
Further Information

Publication History

Received07 August 1998

Accepted after resubmission18 November 1998

Publication Date:
09 December 2017 (online)

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Summary

HL-60 cells treated by PMA develop the monocyte adherent pheno-type and synthesize plasminogen activator inhibitor type-1 (PAI-1). We focused our study on the identification of the PMA-activated protein kinase C (PKC) isoform and its downstream transduction pathway activating PAI-1 synthesis. Acquisition of the monocytic phenotype was evidenced by cell adherence (90-95%) and a sharp increase of CD 36 and receptor for urokinase plasminogen activator (uPAR) surface expression. Ro 31-8220, a specific inhibitor of PKC, prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion. To identify the PKC isoform, we took advantage of the HL-525 cell line, an HL-60 cell variant deficient in PKCβ gene expression. This defect prevents PMA to induce the differentiation process. HL-525 stimulated by PMA did not synthesize PAI-1 nor become adherent. However, in HL-525 cells either pretreated by retinoic acid that reinduces PKCβ gene expression or transfected with PKCβ cDNA, PMA significantly activated PAI-1 synthesis and adhesion of cells. Immunoblotting of active Mitogen Activated Protein Kinase (MAPK) p42/p44 in HL-60 cells showed a preferential and sustained activation of the p42 isoform by PMA over the p44 isoform. Ro 31-8220 significantly attenuated this activation. PD 098059 and U0126, both highly specific MEK inhibitors, efficiently prevented PMA-induced PAI-1 synthesis (mRNA and protein levels) and cell adhesion whereas SB203580, a specific inhibitor of stress-activated MAPK p38, did not. Results obtained from HL-60 and HL-525 cells indicate that the PMA-activated transduction pathway of uPAR expression involves a PKC isoform other than PKCβ.

In conclusion, we propose that the pathway PKCβ-MEK-MAPK p42 is a potential linear route for PAI-1 synthesis leading to morphological changes and adherence linked to PMA-induced differentiation in HL-60 cells.

 

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