Bone morphogenetic protein-7 inhibits constitutive and interleukin-1β-induced monocyte chemoattractant protein-1 expression in human mesangial cells:: Role for JNK/AP-1 pathway

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 antiinflammatory 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-1beta-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-1beta-induced monocyte chemotactic activity released from the mesangial cells. We examined the role of transcription factors NF-kappaB and AP-1 in BMP-7 inhibition of IL-1beta-induced MCP-1 expression. IL-1beta increased NF-kappaB and AP-1 activity and both transcription factors mediated IL-1beta-induced MCP-1 expression in mesangial cells. BMP-7 inhibited IL-1beta-induced AP-1 activity in a concentration-dependent manner. In contrast, IL-1beta-induced NF-kappaB activity and IkappaBalpha degradation were not affected by BMP-7. Furthermore, IL-1beta-induced phosphorylation of c-Jun N-terminal kinase was inhibited by BMP-7. These data suggest that BMP-7 inhibits constitutive and IL-1beta-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.