Effects of anti-rheumatic gold salts on NF-κB mobilization and tumour necrosis factor-alpha (TNF-α)-induced neutrophil-dependent cytotoxicity for human endothelial cells

Johan Bratt, John D Belcher, Gregory M Vercellotti, J. Palmblad

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30 Citations (Scopus)

Abstract

We have previously shown that the gold-containing disease-modifying anti-rheumatic drugs, auranofin (AF) and gold sodium aurothiomalate (GSTM) reduce human umbilical vein endothelial cell (HUVEC) adhesion molecule expression and neutrophil (PMN) adherence. AF diminishes E-selectin and intercellular adhesion molecule-1 (ICAM-1) on cytokine-activated HUVEC, while GSTM decreases only E-selectin. Since tight adhesion is critical for PMN to damage EC, we tested whether these drugs modulated human PMN-mediated injury to TNF-α-activated HUVEC in vitro (as measured by 51Cr release). Here we show that TNF-α caused a prominent PMN-mediated cytotoxicity that was dose- dependently reduced when AF and GSTM were added to the assay system. We also found that a potent inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC) in a dose-dependent manner impaired TNF-α-induced cytotoxicity, indicating a role of NF-κB activation in cytokine-induced endothelial injury. To examine the effects of AF and GSTM on TNF-α-induced NF-κB activation this was measured in HUVEC nuclear extracts by an electrophoretic mobility shift assay. AF, but not GSTM, decreased TNFα-induced NF-κB activation in HUVEC. Thus, in this in vitro model of vasculitis, AF and GSTM dose dependently reduced TNF-α-mediated neutrophil-dependent cytotoxicity for HUVEC, and AF, but not GSTM, inhibited NF-κB mobilization, thereby providing possible mechanisms for effects of AF and GSTM.

Original languageEnglish (US)
Pages (from-to)79-84
Number of pages6
JournalClinical and Experimental Immunology
Volume120
Issue number1
DOIs
StatePublished - Jan 1 2000

Fingerprint

Auranofin
Gold Sodium Thiomalate
Gold
Neutrophils
Endothelial Cells
Tumor Necrosis Factor-alpha
Salts
Human Umbilical Vein Endothelial Cells
E-Selectin
Cytokines
Antirheumatic Agents
Wounds and Injuries
Cell Adhesion Molecules
Electrophoretic Mobility Shift Assay
Intercellular Adhesion Molecule-1
Vasculitis
Cell Extracts

Keywords

  • Anti-rheumatic drugs
  • Cytotoxicity
  • Endothelial cells
  • Gold salts
  • NF-κB

Cite this

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title = "Effects of anti-rheumatic gold salts on NF-κB mobilization and tumour necrosis factor-alpha (TNF-α)-induced neutrophil-dependent cytotoxicity for human endothelial cells",
abstract = "We have previously shown that the gold-containing disease-modifying anti-rheumatic drugs, auranofin (AF) and gold sodium aurothiomalate (GSTM) reduce human umbilical vein endothelial cell (HUVEC) adhesion molecule expression and neutrophil (PMN) adherence. AF diminishes E-selectin and intercellular adhesion molecule-1 (ICAM-1) on cytokine-activated HUVEC, while GSTM decreases only E-selectin. Since tight adhesion is critical for PMN to damage EC, we tested whether these drugs modulated human PMN-mediated injury to TNF-α-activated HUVEC in vitro (as measured by 51Cr release). Here we show that TNF-α caused a prominent PMN-mediated cytotoxicity that was dose- dependently reduced when AF and GSTM were added to the assay system. We also found that a potent inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC) in a dose-dependent manner impaired TNF-α-induced cytotoxicity, indicating a role of NF-κB activation in cytokine-induced endothelial injury. To examine the effects of AF and GSTM on TNF-α-induced NF-κB activation this was measured in HUVEC nuclear extracts by an electrophoretic mobility shift assay. AF, but not GSTM, decreased TNFα-induced NF-κB activation in HUVEC. Thus, in this in vitro model of vasculitis, AF and GSTM dose dependently reduced TNF-α-mediated neutrophil-dependent cytotoxicity for HUVEC, and AF, but not GSTM, inhibited NF-κB mobilization, thereby providing possible mechanisms for effects of AF and GSTM.",
keywords = "Anti-rheumatic drugs, Cytotoxicity, Endothelial cells, Gold salts, NF-κB",
author = "Johan Bratt and Belcher, {John D} and Vercellotti, {Gregory M} and J. Palmblad",
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T1 - Effects of anti-rheumatic gold salts on NF-κB mobilization and tumour necrosis factor-alpha (TNF-α)-induced neutrophil-dependent cytotoxicity for human endothelial cells

AU - Bratt, Johan

AU - Belcher, John D

AU - Vercellotti, Gregory M

AU - Palmblad, J.

PY - 2000/1/1

Y1 - 2000/1/1

N2 - We have previously shown that the gold-containing disease-modifying anti-rheumatic drugs, auranofin (AF) and gold sodium aurothiomalate (GSTM) reduce human umbilical vein endothelial cell (HUVEC) adhesion molecule expression and neutrophil (PMN) adherence. AF diminishes E-selectin and intercellular adhesion molecule-1 (ICAM-1) on cytokine-activated HUVEC, while GSTM decreases only E-selectin. Since tight adhesion is critical for PMN to damage EC, we tested whether these drugs modulated human PMN-mediated injury to TNF-α-activated HUVEC in vitro (as measured by 51Cr release). Here we show that TNF-α caused a prominent PMN-mediated cytotoxicity that was dose- dependently reduced when AF and GSTM were added to the assay system. We also found that a potent inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC) in a dose-dependent manner impaired TNF-α-induced cytotoxicity, indicating a role of NF-κB activation in cytokine-induced endothelial injury. To examine the effects of AF and GSTM on TNF-α-induced NF-κB activation this was measured in HUVEC nuclear extracts by an electrophoretic mobility shift assay. AF, but not GSTM, decreased TNFα-induced NF-κB activation in HUVEC. Thus, in this in vitro model of vasculitis, AF and GSTM dose dependently reduced TNF-α-mediated neutrophil-dependent cytotoxicity for HUVEC, and AF, but not GSTM, inhibited NF-κB mobilization, thereby providing possible mechanisms for effects of AF and GSTM.

AB - We have previously shown that the gold-containing disease-modifying anti-rheumatic drugs, auranofin (AF) and gold sodium aurothiomalate (GSTM) reduce human umbilical vein endothelial cell (HUVEC) adhesion molecule expression and neutrophil (PMN) adherence. AF diminishes E-selectin and intercellular adhesion molecule-1 (ICAM-1) on cytokine-activated HUVEC, while GSTM decreases only E-selectin. Since tight adhesion is critical for PMN to damage EC, we tested whether these drugs modulated human PMN-mediated injury to TNF-α-activated HUVEC in vitro (as measured by 51Cr release). Here we show that TNF-α caused a prominent PMN-mediated cytotoxicity that was dose- dependently reduced when AF and GSTM were added to the assay system. We also found that a potent inhibitor of NF-κB, pyrrolidine dithiocarbamate (PDTC) in a dose-dependent manner impaired TNF-α-induced cytotoxicity, indicating a role of NF-κB activation in cytokine-induced endothelial injury. To examine the effects of AF and GSTM on TNF-α-induced NF-κB activation this was measured in HUVEC nuclear extracts by an electrophoretic mobility shift assay. AF, but not GSTM, decreased TNFα-induced NF-κB activation in HUVEC. Thus, in this in vitro model of vasculitis, AF and GSTM dose dependently reduced TNF-α-mediated neutrophil-dependent cytotoxicity for HUVEC, and AF, but not GSTM, inhibited NF-κB mobilization, thereby providing possible mechanisms for effects of AF and GSTM.

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