title: Bone morphogenic protein-7 inhibits monocyte-stimulated TGF-beta1 generation in renal proximal tubular epithelial cells.
abstract: It has been demonstrated that bone morphogenic protein-7 (BMP-7) stimulates formation of hyaluronan (HA)-based cables on the cell surface of renal proximal tubular cells and that these cables mediate monocyte binding. Furthermore, interaction of monocytes with proximal tubule cell (PTC) surface intracellular adhesion molecule (ICAM) stimulates the synthesis of TGF-beta1. This study examined the effect of BMP-7 on monocyte-stimulated TGF-beta1 synthesis under conditions of basal and stimulated ICAM expression. Monocyte (U937 cells)-dependent stimulation of TGF-beta1 promoter activity and protein synthesis was reduced by addition of BMP-7 for 24 h before addition of U937 cells. Removal of cell surface HA or inhibition of monocyte interaction with HA using antibody to CD44 prevented this effect of BMP-7. These data suggest that BMP-7 enhances HA-dependent binding and reduces ICAM-dependent binding, which is known to stimulate TGF-beta1 synthesis. This hypothesis was examined further by stimulation of PTC ICAM expression by TNF-alpha. After TNF-alpha stimulation, monocyte-dependent TGF-beta1 synthesis increased. This was abrogated by inhibition of ICAM-CD18 interactions. TNF-alpha stimulation alone did not increase TGF-beta1 synthesis. TNF-alpha stimulation of PTC in the presence of BMP-7 failed to increase monocyte-dependent TGF-beta1 stimulation. Although stimulation of PTC by BMP-7 alone decreased cell surface ICAM expression, it did not affect TNF-alpha-induced ICAM expression. The effect of BMP-7 on TGF-beta1 synthesis in TNF-alpha-stimulated cells was abrogated by disruption of CD44-HA interactions, suggesting that it was due to increased monocyte binding to HA on the cell surface.
authors.affiliation: Institute of Nephrology, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, United Kingdom.
authors.forename: Xiao Liang
authors.initials: XL
authors.lastname: Zhang
authors.forename: Wisam
authors.initials: W
authors.lastname: Selbi
authors.forename: Carol
authors.initials: C
authors.lastname: de la Motte
authors.forename: Vincent
authors.initials: V
authors.lastname: Hascall
authors.forename: Aled O
authors.initials: AO
authors.lastname: Phillips
mesh_terms: D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology*; D002448:Cell Adhesion / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells
chemical_list: C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D018960:Hyaluronan Receptors; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D006820:Hyaluronic Acid