Cytokine-specific regulation of urokinase receptor (CD87) expression by U937 mononuclear phagocytes.
Mononuclear phagocytes concentrate urokinase-type plasminogen activator (uPA) at the cell surface by expressing membrane uPA receptors (uPAR). This study examines the ability of exogenous cytokines to alter expression of membrane-associated uPA and uPAR in U937 mononuclear phagocytes. Cells were stimulated with recombinant interferon gamma (IFN gamma) or tumor necrosis factor alpha (TNF alpha), followed by immunolabeling for uPA or uPAR and flow cytometry. IFN gamma increased surface uPA 2.2-fold relative to unstimulated controls (P < .001), whereas TNF alpha had no significant effect. Likewise, maximal uPA binding capacity was increased 2.8-fold by IFN gamma (P < .02), but was not affected by TNF alpha. In unstimulated cells, 50% of receptors were occupied by endogenously generated uPA, and this proportion was not affected by either cytokine. IFN gamma upregulated uPAR 2.1-fold relative to unstimulated controls (P < .001), whereas TNF alpha had no effect. In contrast to effects on surface protein, TNF alpha induced a substantial increase in uPAR mRNA, equaling the effect of IFN gamma. In addition, both cytokines doubled the intracellular uPAR pool (P < .01). By contrast, TNF alpha induced a 2.5-fold increase in the level of uPAR protein released into conditioned medium (compared with unstimulated cells), whereas IFN gamma had no effect. These results indicate that uPAR expression is regulated in a cytokine-specific fashion. Some stimuli, such as TNF alpha, may increase uPAR synthetic activity without a corresponding change in membrane expression, because of enhanced release of uPAR from the cell. Cytokine-specific modulation of uPAR may be important in regulating the function of mononuclear phagocytes in inflammation and tissue repair.
Sitrin
R G
RG
Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor 48109-0360.
Todd
R F
RF
Mizukami
I F
IF
Gross
T J
TJ
Shollenberger
S B
SB
Gyetko
M R
MR
D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D010586:Phagocytes / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011956:Receptors, Cell Surface / Q000096:biosynthesis*; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
C524898:PLAUR protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D014568:Urokinase-Type Plasminogen Activator