HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Plasminogen activator inhibitor type 2: a regulator of monocyte proliferation and differentiation

We have explored the role of plasminogen activator inhibitor type 2 (PAI-2) in THP-1 monocyte–like cells. These cells possess a mutation in the PAI-2 gene and do not produce an active PAI-2 protein. Transfection of THP-1 cells with plasmids expressing active PAI-2 reduced the cells’ inherent adhesive properties and decreased the rate of cell proliferation. THP-1 cells expressing active PAI-2 also displayed an altered phenotype in response to phorbol ester–induced differentiation that was concomitant with a reduction in CD14 expression. THP-1 cells transfected with a variant PAI-2 containing a mutation in the reactive center (PAI-2Ala380) displayed no noticeable change in any of these parameters, suggesting the involvement of a PAI-2–sensitive serine protease(s). The antiproliferative effect of PAI-2 was attenuated by treating the PAI-2–expressing THP-1 cells with recombinant urokinase (u-PA), suggesting that PAI-2 was disruptive of a u-PA/u-PA receptor signaling pathway initiated on the cell surface. Consistent with this, treatment of wildtype THP-1 cells with recombinant PAI-2 also caused a reduction in cellular proliferation. These results implicate endogenous PAI-2 as a modulator of monocyte adhesion, proliferation, and differentiation. (Blood. 2002;99:2810-2818)