Iron chelators inhibit VCAM-1 expression in human dermal microvascular endothelial cells

JOURNAL OF INVESTIGATIVE DERMATOLOGY

卷:120

Article

Koo, SW ; Casper, KA ; Otto, KB ; Gira, AK ; Swerlick, RA

关键词: endothelium;    gene regulation;    adhesion;    iron;   

DOI  :  10.1046/j.1523-1747.2003.12144.x

来源: Elsevier

【 摘 要 】

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 TNFalpha-induced VCAM-1 gene expression, human dermal microvascular endothelial cells (HDMEC) were stimulated with TNFalpha 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 TNFalpha-mediated up-regulation of VCAM-1 heterogeneous nuclear RNA. Pretreatment of HDMEC with DP prior to TNFalpha treatment had no effect on p65 nuclear localization, DNA binding, or serine phosphorylation. DP pretreatment inhibited TNFalpha- and IFNgamma-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. IkBalpha, 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 TNFalpha mediated VCAM-1 induction in HDMEC, and the target for iron effects may be IRF-1, NF-kB, and potentially chromatin remodeling.

【 授权许可】

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