In vitro anti-inflammatory effects and immunomodulation by gemifloxacin in stimulated human THP-1 monocytes.
Cultured human THP-1 monocytes were exposed to serial concentrations of gemifloxacin over 4 h after pre-stimulation with zymogen A for 1 h or Staphylococcus aureus for 2 h. The following parameters were assessed: pH, phagocytosis, c-AMP, NO, TNFalpha, IL-1, IL-6, IL-8 and H2O2 levels, enzyme activities of protein kinase C, NADPH oxidase, SOD, gluthathion reductase, NAG and cathepsin D as well as lipid peroxidation. The reversiblity of these changes was determined in the presence of known blockers of the phagocytic process. The effects of gemifloxacin on DNA synthesis and killing of S. aureus was assessed in bacteria alone and in those bacteria phagocytosed by THP-1 monocytes over 24 h. Gemifloxacin in stimulated THP-1 monocytes over the first 30 min caused an increase in c-AMP, NO, H2O2 and TNFalpha levels and protein kinase C, NADPH oxidase, glutathione reductase, NAG and cathepsin D activities. The pH became more acidic and phagocytosis was stimulated. These parameters were reversed at 1 h and continued to decline until 4 h. Lipid peroxidation was at the highest levels at 1 h and IL-8 levels at 2 h. DNA synthesis and bacterial growth were suppressed at 2 h in both S. aureus alone and bacteria phagocytosed by THP-1 monocytes. These effects were at a higher magnitude at 24 h. Gemifloxacin initiates a phagocyticidal effect of THP-1 monocytes at an early time of 30 min which plays a role in killing bacteria but a higher magnitude of killing of bacteria occurs later by a standard static mechanism. This early action of gemifloxacin should decrease the spread of infection and the inflammatory response since the tissue destruction process was attenuated at 4 h.
Hall
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Divison of Medicinal Chemistry, School of Pharmacy, University of North Carolina, Chapel Hill 27599-7360, USA. iris_hall@unc.edu
Schwab
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Ward
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Ives
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D000900:Anti-Bacterial Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D024841:Fluoroquinolones / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077735:Gemifloxacin; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007155:Immunologic Factors; D015227:Lipid Peroxidation / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009287:Naphthyridines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D016877:Oxidants / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000502:physiology; D016897:Respiratory Burst / Q000187:drug effects
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D024841:Fluoroquinolones; D007155:Immunologic Factors; D009287:Naphthyridines; D019384:Nucleic Acid Synthesis Inhibitors; D016877:Oxidants; D006861:Hydrogen Peroxide; D000077735:Gemifloxacin