Iron Chelators Inhibit VCAM-1 Expression in Human Dermal Microvascular Endothelial Cells
Vascular cell adhesion molecule (VCAM)-1 expression may be coupled to redox-sensitive regulatory pathways, and iron may play a role in generation of reactive oxygen species that participate in these signaling pathways. To investigate the role of iron in TNFα-induced VCAM-1 gene expression, human der...
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Published in | Journal of investigative dermatology Vol. 120; no. 5; pp. 871 - 879 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Danvers, MA
Elsevier Inc
01.05.2003
Nature Publishing Elsevier Limited |
Subjects | |
Online Access | Get full text |
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Summary: | Vascular cell adhesion molecule (VCAM)-1 expression may be coupled to redox-sensitive regulatory pathways, and iron may play a role in generation of reactive oxygen species that participate in these signaling pathways. To investigate the role of iron in TNFα-induced VCAM-1 gene expression, human dermal microvascular endothelial cells (HDMEC) were stimulated with TNFα in the presence of iron chelators and examined for expression of VCAM-1. The iron chelators dipyridyl (DP) and desferoxamine (DFO) inhibited VCAM-1 protein and mRNA induction in a concentration- and time-dependent manner. The induction of VCAM-1 was not inhibited by nonmetal binding reactive oxygen species (ROS) scavengers, implying a direct effect of iron in the expression of these adhesion molecules. The effect of iron was mediated at the level of gene transcription since pretreatment with DP abrogated the TNFα-mediated up-regulation of VCAM-1 heterogeneous nuclear RNA. Pretreatment of HDMEC with DP prior to TNFα treatment had no effect on p65 nuclear localization, DNA binding, or serine phosphorylation. DP pretreatment inhibited TNFα- and IFNγ-mediated interferon regulatory factor 1 (IRF-1) protein expression, although restoration of IRF-1 expression failed to reconstitute VCAM-1 expression. DP treatment also blocked VCAM-1 induction in human umbilical vein endothelium and blocked induction of a host of NF-kB activated genes in HDMEC including ICAM-1, IL-8, and tissue factor. IkBα, an NF-kB inducible and constitutively accessible gene not requiring chromatin remodeling for transcription, was not affected by DP treatment. These data suggest that iron plays a critical role in TNFα mediated VCAM-1 induction in HDMEC, and the target for iron effects may be IRF-1, NF-kB, and potentially chromatin remodeling. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-202X 1523-1747 |
DOI: | 10.1046/j.1523-1747.2003.12144.x |