Monocyte urokinase expression: modulation by interleukins

This study delineates the regulatory effect of interleukin-1 (IL-1) and interleukin-2 (IL-2) on monocyte plasminogen activator (PA) activity. Mononuclear phagocytes regulate net PA activity by modulating the expression of urokinase-type PA (uPA) and a specific plasminogen activator inhibitor, PAI-2. To understand the regulation of mononuclear phagocyte PA activity, it is important to compare the expression of uPA and PAI-2. In this study, we determined the relative abundance of secreted PA and PA inhibitor activity in human monocyte-conditioned medium after stimulation with human recombinant IL-1 or IL-2. In agreement with our previous description of tumor necrosis factor-alpha and interferon-gamma stimulation of mononuclear phagocytes, we found no detectable PA activity in conditioned medium. Both IL-1 and IL-2 had dose-dependent effects, significantly up-regulating PA inhibitor activity in monocyte-conditioned medium (up to 11-fold). To further investigate the mechanism underlying this effect, Northern blot analysis was done to measure steady-state mRNA for uPA and PAI-2. Consistent with the increase in secreted PA inhibitor activity, we found that both IL-1 and IL-2 significantly increased steady-state mRNA for PAI-2. In addition, however, both IL-1 and IL-2 increased steady-state mRNA for uPA. IL-1 appears to increase mRNA for uPA to a greater extent than does IL-2. We conclude that IL-1 and IL-2 modulate monocyte proteolytic activity by increasing expression of uPA and PAI-2 with a resultant predominance of PAI-2. We further conclude that cytokine-specific regulation of plasminogen activity is achieved partly by varying the proportionate expression of uPA and PAI-2.