The mechanism of action of the antiinflammatory agents dexamethasone and Auranofin in human polymorphonuclear leukocytes.
Human polymorphonuclear neutrophils (PMN) were treated with the antiinflammatory agents dexamethasone or Auranofin. PMN treated with dexamethasone in a dose range of 0.25-1 microM or Auranofin, 5-15 mM, were stimulated with 10(-7)M N-formyl-methionyl-leucyl-phenylalanine (FMLP). These agents were shown to inhibit the functional responses of degranulation and superoxide production in a dose-dependent manner. Similarly, the change in electrophoretic mobility, reflecting cell surface charge, was blocked. While both agents inhibited change in the fluorescence of the calcium chelate probe chlorotetracycline (CTC), the pattern of inhibition was significantly different. Dexamethasone appeared to inhibit the CTC response during its latter phases, while Auranofin inhibited all aspects of the CTC response. Auranofin was additionally shown to significantly decrease specific binding of FMLP, as well as the number of FMLP receptors. The two agents thus appear to act by different mechanisms. Dexamethasone is shown to have an effect on membrane-bound calcium release as measured by CTC, while Auranofin interferes with receptor binding.
D001310:Auranofin; D006051:Aurothioglucose / Q000031:analogs & derivatives* / Q000494:pharmacology; D002751:Chlortetracycline / Q000494:pharmacology; D003571:Cytochalasin B / Q000494:pharmacology; D003594:Cytoplasmic Granules / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004586:Electrophoresis; D005453:Fluorescence; D006046:Gold; D006801:Humans; D007781:Lactoferrin / Q000378:metabolism; D009113:Muramidase / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology; D011956:Receptors, Cell Surface / Q000032:analysis; D044042:Receptors, Formyl Peptide; D013481:Superoxides / Q000378:metabolism
D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D013481:Superoxides; D006051:Aurothioglucose; D003571:Cytochalasin B; D001310:Auranofin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D006046:Gold; D003907:Dexamethasone; D009113:Muramidase; D007781:Lactoferrin; D002751:Chlortetracycline