Human platelets stimulate mesangial cells to produce monocyte chemoattractant protein-1 via the CD40/CD40 ligand pathway and may amplify glomerular injury.
Platelets are thought to play an important role in the initiation and the progression of a variety of glomerulonephritides. This study examined whether platelets induce production of monocyte chemoattractant protein-1 (MCP-1), a chemokine involved in leukocyte recruitment and glomerular injury, by cultured human mesangial cells (MC). To this end, platelets isolated from normal human donors were cocultured with MC at various ratios. MCP-1 synthesis was evaluated by quantitative real-time PCR and enzyme-linked immunosorbent assay. Platelets at 1:100 ratio (MC to platelets) induced an approximately 20-fold increase in mesangial MCP-1 mRNA and protein expression through an obligatory cell-to-cell contact-dependent mechanism. Importantly, blockade of the CD40/CD40 ligand (CD40L) pathway with neutralizing antibodies decreased MCP-1 production by approximately 60%. It was confirmed that CD40 was functionally expressed on MC. Gel-shift assays and inhibitors of phosphorylation were used to demonstrate that activation of p38 mitogen-activated protein kinase, protein tyrosine kinases, and nuclear factor-kappa B activation were essential for MCP-1 production. These data indicate that platelet/MC contact stimulates the production of MCP-1 and may contribute to glomerular inflammatory responses by recruiting leukocytes from the peripheral blood.
Tanaka
Takaharu
T
Third Department of Internal Medicine, Gunma University School of Medicine, Maebashi, Gunma, Japan.
Kuroiwa
Takashi
T
Ikeuchi
Hidekazu
H
Ota
Fumie
F
Kaneko
Yoriaki
Y
Ueki
Kazue
K
Tsukada
Yoshito
Y
McInnes
Iain B
IB
Boumpas
Dimitrios T
DT
Nojima
Yoshihisa
Y
D001792:Blood Platelets / Q000502:physiology*; D019013:CD40 Antigens / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism*; D002450:Cell Communication; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D005921:Glomerulonephritis / Q000473:pathology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases
D019013:CD40 Antigens; D018932:Chemokine CCL2; D016328:NF-kappa B; D023201:CD40 Ligand; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases