title: The MCP-1/CCR2 system has direct proinflammatory effects in human mesangial cells.
abstract: Both inflammatory and haemodynamic factors have been implicated in the pathogenesis of diabetic and other progressive glomerulopathies. Mesangial cell exposure to mechanical stretch induces both intercellular adhesion molecule 1 (ICAM-1) and monocyte chemoattractant protein-1 (MCP-1) expression. CC Chemokine receptor 2 (CCR2), the cognate MCP-1 receptor, has been recently demonstrated in human mesangial cells (HMCs). We tested whether MCP-1 binding to CCR2 affects ICAM-1 expression in HMCs and, secondly, if stretch-induced ICAM-1 is mediated by MCP-1 via an autocrine mechanism. Serum-deprived HMCs were exposed to either rh-MCP-1 (0.1-1-10-50-100 ng/ml) or mechanical stretch in the presence and in the absence of RS102895, a specific CCR2 inhibitor. ICAM-1 expression was assessed both by immunofluorescence and cytofluorimetry. Monocyte-HMC interaction was tested by adhesion assay. CCR2 expression was studied by reverse transcriptase-polymerase chain reaction, immunoblotting, and flow cytometry. HMCs exposure to rh-MCP-1 induced a significant twofold increase in ICAM-1 expression at 24 h, leading to enhanced monocyte adhesion. This effect occurred via the CCR2 receptor as CCR2 was expressed in HMCs and CCR2 blockade prevented ICAM-1 upregulation. Stretch-induced ICAM-1 expression was not altered by CCR2 blockade and stretch significantly reduced CCR2 mRNA and protein expression via an MCP-1-independent mechanism. In conclusion, stretch and MCP-1 independently induce ICAM-1 expression in HMCs. Stretch-induced CCR2 downregulation may favour MCP-1 paracrine activity.
authors.affiliation: Department of Internal Medicine, University of Turin, 14 Corso AM Dogliotti, 10126 Turin, Italy. sara_giunti@katamail.com
authors.forename: S
authors.initials: S
authors.lastname: Giunti
authors.forename: S
authors.initials: S
authors.lastname: Pinach
authors.forename: L
authors.initials: L
authors.lastname: Arnaldi
authors.forename: G
authors.initials: G
authors.lastname: Viberti
authors.forename: P C
authors.initials: PC
authors.lastname: Perin
authors.forename: G
authors.initials: G
authors.lastname: Camussi
authors.forename: G
authors.initials: G
authors.lastname: Gruden
mesh_terms: D002448:Cell Adhesion; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D050527:Mesangial Cells / Q000166:cytology / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D013314:Stress, Mechanical
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D012333:RNA, Messenger; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018799:Intercellular Adhesion Molecule-1