Abstract
Bone morphogenetic protein-7 (BMP-7), which belongs to the TGF-beta superfamily, has been shown to reduce macrophage infiltration and tissue injury in animal models of inflammatory renal disease. To explore the mechanism involved in the anti-inflammatory effect, we investigated the effect of BMP-7 on monocyte chemoattractant protein-1 (MCP-1) expression in cultured human mesangial cells. BMP- 7 significantly inhibited constitutive and IL-1 beta-induced MCP-1 protein production and MCP-1 mRNA expression by mesangial cells in a time- and concentration-dependent manner. BMP-7 also inhibited IL-1 beta-induced monocyte chemotactic activity released from the mesangial cells. We examined the role of transcription factors NF-kappa B and AP-1 in BMP-7 inhibition of IL-1 beta-induced MCP-1 expression. IL-1 beta increased NF-kappa B and AP-1 activity and both transcription factors mediated IL-1 beta-induced MCP-1 expression in mesangial cells. BMP-7 inhibited IL-1 beta-induced AP-1 activity in a concentration-dependent manner. In contrast, IL-1 beta-induced NF-kappa B activity and I kappa B alpha degradation were not affected by BMP-7. Furthermore, IL-1 beta-induced phosphorylation of c-Jun N-terminal kinase was inhibited by BMP-7. These data suggest that BMP-7 inhibits constitutive and IL-1 beta-induced MCP-1 expression in human mesangial cells partly by inhibiting c-Jun N-terminal kinase activity and subsequent AP-1 activity, and provide new insight into the therapeutic potential of BMP-7 in the inflammatory renal diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Bone Morphogenetic Protein 7
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Bone Morphogenetic Proteins / pharmacology
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Bone Morphogenetic Proteins / physiology*
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Cells, Cultured
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Chemokine CCL2 / antagonists & inhibitors*
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Chemokine CCL2 / biosynthesis*
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Chemokine CCL2 / metabolism
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Chemokine CCL2 / physiology
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Enzyme Inhibitors / pharmacology
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Glomerular Mesangium / cytology
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Glomerular Mesangium / enzymology
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Glomerular Mesangium / immunology*
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Glomerular Mesangium / metabolism
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Humans
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Interleukin-1 / antagonists & inhibitors
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Interleukin-1 / pharmacology*
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Mitogen-Activated Protein Kinases / physiology*
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NF-kappa B / antagonists & inhibitors
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NF-kappa B / metabolism
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Phosphorylation
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Protein Synthesis Inhibitors / pharmacology
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RNA, Messenger / antagonists & inhibitors
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RNA, Messenger / biosynthesis
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Recombinant Proteins / pharmacology
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Signal Transduction / immunology*
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Transcription Factor AP-1 / antagonists & inhibitors
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Transcription Factor AP-1 / metabolism
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Transcription Factor AP-1 / physiology*
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Transforming Growth Factor beta*
Substances
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BMP7 protein, human
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Bone Morphogenetic Protein 7
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Bone Morphogenetic Proteins
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Chemokine CCL2
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Enzyme Inhibitors
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Interleukin-1
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NF-kappa B
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Protein Synthesis Inhibitors
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RNA, Messenger
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Recombinant Proteins
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Transcription Factor AP-1
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Transforming Growth Factor beta
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases