Journal Article

Dexamethasone regulates AP-1 to repress TNF-α induced MCP-1 production in human glomerular endothelial cells

Su-Kil Park, Won Seok Yang, Nam Jung Han, Sang Koo Lee, Hanjong Ahn, In Kyu Lee, Joong Yeol Park, Ki-Up Lee and Jae Dam Lee

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 19, issue 2, pages 312-319
Published in print February 2004 | ISSN: 0931-0509
Published online February 2004 | e-ISSN: 1460-2385 | DOI: http://dx.doi.org/10.1093/ndt/gfg583
Dexamethasone regulates AP-1 to repress TNF-α induced MCP-1 production in human glomerular endothelial cells

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Background. Glomerular endothelial cells play a role in the pathogenesis of glomerulonephritis by producing chemotactic factors. We investigated the role of NF-κB and AP-1 in tumour necrosis factor α (TNF-α) induced monocyte chemoattractant protein 1 (MCP-1) production in cultured human glomerular endothelial cells (HGEC). We also examined whether or not these processes could be modified by glucocorticoid.

Methods. MCP-1 protein and mRNA levels were measured by ELISA and northern blot. NF-κB and AP-1 binding activity were assessed by electrophoretic mobility shift assay. Cytosolic IκBα and nuclear p65 protein were evaluated by western blot. For specific inhibition of NF-κB or AP-1, we used a decoy oligodeoxynucleotide.

Results. TNF-α (10 ng/ml) increased MCP-1 mRNA expression in HGEC and also the release of MCP-1 protein into culture media. These effects could be partially inhibited by dexamethasone (10 nM). TNF-α induced MCP-1 production appeared to be NF-κB and AP-1 interdependent, based on the following results. (i) TNF-α increased NF-κB and AP-1 binding activity. (ii) Both NF-κB decoy oligodeoxynucleotide and AP-1 decoy oligodeoxynucleotide partially suppressed TNF-α induced MCP-1 mRNA expression. On the other hand, dexamethasone decreased TNF-α induced DNA-binding activity of AP-1 without an effect on the DNA-binding activity of NF-κB, cytosolic IκBα degradation or p65 nuclear translocation.

Conclusions. These data demonstrate that while TNF-α induced MCP-1 production is mediated by the cooperative action of NF-κB and AP-1 in HGEC, dexamethasone represses TNF-α induced MCP-1 production via suppression of AP-1 binding activity.

Keywords: AP-1; decoy oligonucleotide; dexamethasone; endothelial cells; MCP-1; NF-κB

Journal Article.  4056 words.  Illustrated.

Subjects: Nephrology

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