Glomerular mesangial cells (MCs) are central to the pathogenesis of progressive glomeruli-associated renal diseases. However, molecular mechanisms underlying changes in MC functions still remain poorly understood. Here, we show that in MCs, the urokinase-type plasminogen activator (uPA) induces, via its specific receptor (uPAR, CD87), upregulated expression of the complement anaphylatoxin C5a receptor (C5aR, CD88), and modulates C5a-dependent functional responses. This effect is mediated via the interaction of the uPA-specific receptor (uPAR, CD87) and gp130, a signal transducing subunit of the receptor complexes for the IL-6 cytokine family. The Janus kinase Tyk2 and the transcription factor Stat3 serve as downstream components in the signaling cascade resulting in upregulation of C5aR expression. In vivo, expression of C5aR and uPAR was increased in the mesangium of wild-type mice in a lipopolysaccharide (LPS)-induced model of inflammation, whereas in uPAR–/– animals C5aR expression remained unchanged. This is the first demonstration in vitro and in vivo that uPA acts in MCs as a modulator of immune responses via control of immune-competent receptors. The data suggest a novel role for uPA/uPAR in glomeruli-associated renal failure via a signaling cross-talk between the fibrinolytic and immune systems.

J. Zwirner, who produced the 20/70-antibody is his laboratory, is retracting his authorship from this paper. The reasons for the retraction are (1) he was not informed about the manuscript before it was published and (2) he could not observe, under the experimental conditions used in his laboratory, the immunoreactivity described in Fig. 10. All authors accept this decision, which is the result of an agreement mediated by the Ombudsman of the German Research Council.

After vascular injury, a remodeling process occurs that features leukocyte migration and infiltration. Loss of endothelial integrity allows the leukocytes to interact with vascular smooth muscle cells (VSMCs) and to elicit "marching orders"; however, the signaling processes are poorly understood. We found that human monocytes inhibit VSMC proliferation and induce a migratory potential. The monocytes signal the VSMCs through the urokinase-type plasminogen activator (uPA). The VSMC uPA receptor (uPAR) receives the signal and activates the transcription factor Stat1 that, in turn, mediates the antiproliferative effects. These results provide the first evidence that monocytes signal VSMCs by mechanisms involving the fibrinolytic system, and they imply an important link between the uPA/uPARrelated signaling machinery and human vascular disease. IntroductionRestenosis after percutaneous vascular therapeutic interventions remains unresolved. 1,2 After vascular injury, the endothelial integrity is disturbed and monocytes infiltrate the injured vessels. The monocytes promote an inflammatory response by generating migratory and proliferative signals that converge on vascular smooth muscle cells (VSMCs). The VSMCs first migrate to the normally thin intimal layer and thereafter proliferate, causing neointimal formation and restenosis. 3,4 Although VSMC proliferation was reported in most animal models of vascular remodeling, few proliferating VSMCs were detected in human lesions. This finding implies an antiproliferative mechanism for VSMC growth control, at least during the early phase of the remodeling process. 5 We showed earlier that the urokinase-type plasminogen activator (uPA) and its receptor (uPAR) are up-regulated on VSMCmonocyte interaction in a coculture model and contribute to increased VSMC motility. 6 uPA is an unusual molecule of dual function that switches from the proteolytic enzyme to the signalinducing ligand, depending on external stimuli. 7,8 The uPA/uPAR system has a nonproteolytic role in vitro and in vivo that extends beyond its role in fibrinolysis. 9,10 We investigated the mechanisms underlying changes in VSMC behavior on interaction with monocytes. We found that the monocytes express uPA to convey an antiproliferative signal to the VSMCs through their uPAR receptor. This signaling is mediated by activation of the VSMC transcription factor signal transducer and activator of transcription 1 (Stat1). Our study may explain the increased VSMC migratory potential and the absence of VSMC proliferation observed at the early step of a remodeling process of the vessel wall after vascular injury in humans. Conceivably, a useful strategy for therapeutic intervention could ensue. Materials and methodsCell culture, monocyte isolation, coculture, and cell separation after coculture Human vascular smooth muscle cells from coronary artery were obtained from Clonetics (San Diego, CA). Cells were grown in Smooth Muscle Medium-2 (SmGM2) medium (Clonetics) supplemented with 5% fetal bovine serum and were used between...