Differential regulation of vascular cell adhesion molecule-1 gene transcription by tumor necrosis factor alpha and interleukin-1 alpha in dermal microvascular endothelial cells

Gille, Jens; Swerlick, RA; Lawley, T J; Caughman, S. Wright

doi:10.1182/blood.v87.1.211.bloodjournal871211

Cited by 5 publications

(4 citation statements)

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“…It is possible that iron blocked VCAM-1 induction in HDMEC via a mechanism completely independent of NF-kB. This is quite unlikely given previous studies of TNFa mediated VCAM-1 gene expression in this context showing a strict dependence on NF-kB (Iademarco et al, 1992;Neish et al, 1995;Gille et al, 1996). An alternative mechanism may be an iron dependent process regulating chromatin modi¢cations and accessibility.…”

Section: Iron Chelators Do Not Inhibit Nf-kb Phosphorylationmentioning

confidence: 93%

“…Electrophoretic mobility-shift assay (EMSA) Con£uent 5A32 HDMEC were treated with 500 U/ml TNFa for 2 h after preincubation with 500 mM DP for 24 h. Nuclear proteins were extracted and EMSA performed as described previously (Gille et al, 1996). The VCAM-1 oligonucleotide was synthesized to encompass the two NF-kB-like sites of the human VCAM-1 promoter.…”

Section: Methodsmentioning

confidence: 99%

“…The double stranded oligonucleotide was 5 0 -end labeled using the forward reaction with T4 polynucleotide kinase (Gibco/BRL). The DNA binding reaction was performed under the conditions described previously (Gille et al, 1996).…”

Section: Methodsmentioning

confidence: 99%

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Iron Chelators Inhibit VCAM-1 Expression in Human Dermal Microvascular Endothelial Cells

Koo

Casper

Otto

et al. 2003

Journal of Investigative Dermatology

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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 TNF alpha-induced VCAM-1 gene expression, human dermal microvascular endothelial cells (HDMEC) were stimulated with TNF alpha 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 TNF alpha-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 TNF alpha- and IFN gamma-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. I kappa B alpha, an NF-kappa B 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 TNF alpha mediated VCAM-1 induction in HDMEC, and the target for iron effects may be IRF-1, NF-kappa B, and potentially chromatin remodeling.

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Section: Iron Chelators Do Not Inhibit Nf-kb Phosphorylationmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

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Iron Chelators Inhibit VCAM-1 Expression in Human Dermal Microvascular Endothelial Cells

Koo

Casper

Otto

et al. 2003

Journal of Investigative Dermatology

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“…The ®nal targets of cell surface signals are often the activated proteins that associate with DNA regulatory elements and regulate transcription. ICAM-1 and VCAM-1 are highly regulated at the transcriptional level by a number of mediators (Neish et al, 1992;Marui et al, 1993;Cornelius et al, 1994;Gille et al, 1996;Duff et al, 1997;Paxton et al, 1997). Transcription of ICAM-1 and VCAM-1 induced by TNFa is modulated by distinct members of the Rel family.…”

Section: Transcriptional Mechanisms By Which Sp Modulates Cellular Adhesion Molecule Gene Expression In Hdmecmentioning

confidence: 99%

Neural Regulation of Endothelial Cell-Mediated Inflammation

Lindsey

Caughman

Olerud

et al. 2000

Journal of Investigative Dermatology Symposium Proceedings

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There is increasing evidence that the cutaneous neurosensory system can directly modulate inflammatory responses in the skin by the release of neuropeptides such as substance P (SP). Dermal microvascular endothelial cell (DMEC) cellular adhesion molecule (CAM) expression plays a key role in directing leukocyte trafficking during cutaneous inflammatory responses. In recent studies, our laboratory examined the direct effect of SP on DMEC CAM expression and function in vitro and in vivo. Our studies indicate that DMEC express high affinity functional receptors for SP. After exposure to SP, DMEC expressed significant levels of both intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), which was accompanied by increased binding to leukocytes expressing the appropriate integrin counter receptors for these CAM. We then determined the in vivo effect of released neuropeptides on DMEC CAM expression. Our results indicate that the topical cutaneous application of the neuropeptide-releasing agent capsaicin resulted in increased ICAM-1 and VCAM-1 immunostaining of microvascular cells in the skin of human volunteers. Little is known regarding the cellular regulatory events by which SP modulates DMEC CAM expression. Our studies indicate that SP-induced cellular Ca+2 signals led to the activation of the NF-kappaB pathway, resulting in nuclear translocation of p65/p50 heterodimers that bind to high-affinity tandem kappaB sites on the VCAM-1 promoter, whereas SP activation induced NF-AT activation and ICAM-1 DNA binding. Thus, these studies further support the role of the cutaneous neurologic system in modulating inflammatory processes in the skin.

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Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor α and SP proteins

et al. 2003

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Vascular endothelial growth factor (VEGF) is expressed in multiple hormone-dependent cancer cells/tumors. Treatment of ZR-75 breast cancer cells with 17b-estradiol (E2) induced a greater than fourfold increase of VEGF mRNA levels. ZR-75 breast cancer cells were transfected with pVEGF1, a construct containing a À2018 to þ 50 VEGF promoter insert, and E2 induced reporter gene (luciferase) activity. Deletion and mutation analysis of the VEGF gene promoter identified a GC-rich region (À66 to À47) which was required for E2-induced transactivation of pVEGF5, a construct containing the minimal promoter (À66 to þ 54) that exhibited E2-responsiveness. Interactions of nuclear proteins from ZR-75 cells with the proximal GC-rich region of the VEGF gene promoter were investigated by electrophoretic mobility shift and chromatin immunoprecipitation assays. The results demonstrate that both Sp1 and Sp3 proteins bound the GCrich motif (À66 to À47), and estrogen receptor a (ERa) interactions were confirmed by chromatin immunoprecipitation. Moreover, E2-dependent activation of constructs containing proximal and distal GC/GT-rich regions of the VEGF promoter was inhibited in ZR-75 cells transfected with small inhibitory RNAs for Sp1 and Sp3. These results were consistent with a mechanism of hormone activation of VEGF through ERa/Sp1 and ERa/Sp3 interactions with GC-rich motifs.

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Differential regulation of vascular cell adhesion molecule-1 gene transcription by tumor necrosis factor alpha and interleukin-1 alpha in dermal microvascular endothelial cells

Cited by 5 publications

References 0 publications

Iron Chelators Inhibit VCAM-1 Expression in Human Dermal Microvascular Endothelial Cells

Iron Chelators Inhibit VCAM-1 Expression in Human Dermal Microvascular Endothelial Cells

Neural Regulation of Endothelial Cell-Mediated Inflammation

Estrogen regulation of vascular endothelial growth factor gene expression in ZR-75 breast cancer cells through interaction of estrogen receptor α and SP proteins

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