Urokinase-induced activation of the gp130/Tyk2/Stat3 pathway mediates a pro-inflammatory effect in human mesangial cells via expression of the anaphylatoxin C5a receptor.
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.
Shushakova
Nelli
N
Hannover Medical School, Germany.
Tkachuk
Natalia
N
Dangers
Marc
M
Tkachuk
Sergey
S
Park
Joon-Keun
JK
Zwirner
Joerg
J
Hashimoto
Koji
K
Haller
Hermann
H
Dumler
Inna
I
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001692:Biological Transport; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009393:Nephritis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism*; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D053634:TYK2 Kinase; D015534:Trans-Activators / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*
D015703:Antigens, CD; C488033:C5AR1 protein, human; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse; D014568:Urokinase-Type Plasminogen Activator