The soluble D2D3(88-274) fragment of the urokinase receptor inhibits monocyte chemotaxis and integrin-dependent cell adhesion.
We have previously shown that chymotrypsin-cleaved soluble uPAR (D2D3(88-274)) elicits migration of monocytic cells through interaction with FPRL-1, a G protein-coupled receptor that is homologous to the fMLP receptor. Here, we report that D2D3(88-274) also modulates the ability of monocytes to migrate in response to other chemokines. Pretreatment of monocytes with increasing amounts of D2D3(88-274) prevents cell migration in response to MCP-1, RANTES and fMLP. We demonstrate that D2D3(88-274) does not inhibit MCP-1 receptor binding, elicit CCR2 internalization and prevent MCP-1-induced intracellular Ca(2+) increase. Thus, CCR2 receptor desensitization cannot account for D2D3(88-274)-mediated inhibition of MCP-1-induced cell migration. Rather, we show that pretreatment of monocytes with D2D3(88-274) dramatically decreases chemokine-induced integrin-dependent rapid cell adhesion by interacting with FPRL-1. Together, our results indicate that chemokine-dependent cell migration can be regulated not only by homologous and heterologous receptor desensitization, but also by inhibition of integrin-dependent cell adhesion, an important step in cell transmigration.
Furlan
Federico
F
Department of Molecular Biology and Functional Genomics, San Raffaele Scientific Institute, Milan, 20132, Italy.
Orlando
Simone
S
Laudanna
Carlo
C
Resnati
Massimo
M
Basso
Veronica
V
Blasi
Francesco
F
Mondino
Anna
A
D018821:CD18 Antigens / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism / Q000494:pharmacology; D018946:Chemokine CCL5 / Q000378:metabolism / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D009000:Monocytes / Q000378:metabolism / Q000502:physiology*; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D019707:Receptors, Chemokine / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins / Q000494:pharmacology; D012995:Solubility
C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018821:CD18 Antigens; D018932:Chemokine CCL2; D018946:Chemokine CCL5; C105101:FPR2 protein, human; C524898:PLAUR protein, human; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface; D019707:Receptors, Chemokine; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins