Abstract
Sepsis is a systemic reaction to an infection and resulting in excessive production of inflammatory cytokines and chemokines. It sometimes results in septic shock. The present study aimed to identify quinolone antibiotics that can reduce tumor necrosis factor alpha (TNFα) production and to elucidate mechanisms underlying inhibition of TNFα production. We identified quinolone antibiotics reduced TNFα production in lipopolysaccharide (LPS)-stimulated THP-1 cells. Sitafloxacin (STFX) is a broad-spectrum antibiotic of the quinolone class. STFX effectively suppressed TNFα production in LPS-stimulated THP-1 cells in a dose-dependent manner and increased extracellular signal-regulated kinase (ERK) phosphorylation. The percentage of intracellular TNFα increased in LPS-stimulated cells with STFX compared with that in LPS-stimulated cells. TNFα converting enzyme (TACE) released TNFα from the cells, and STFX suppressed TACE phosphorylation and activity. To conclude, one of the mechanisms underlying inhibition of TNFα production in LPS-stimulated THP-1 cells treated with STFX is the inhibition of TNFα release from cells via the suppression of TACE phosphorylation and activity. STFX may kill bacteria and suppress inflammation. Therefore, it can be effective for sepsis treatment.
Highlights
Abbreviations CPFX Ciprofloxacin extended-spectrum betalactamase (ESBL) Extended-spectrum beta-lactamase extracellular signal-regulated kinase (ERK) Extracellular signal-regulated kinase GRNX Garenoxacin IL-8 Interleukin-8 IP-10 Interferon inducible protein LPS Lipopolysaccharide LVFX Levofloxacin MCP-1 Monocyte chemoattractant protein-1 MIP-1α Macrophage inflammatory protein-1α MIP-1β Macrophage inflammatory protein-1β
Tumor necrosis factor alpha
STFX inhibited TNFα production significantly compared with other quinolones
Summary
Abbreviations CPFX Ciprofloxacin ESBL Extended-spectrum beta-lactamase ERK Extracellular signal-regulated kinase GRNX Garenoxacin IL-8 Interleukin-8 IP-10 Interferon inducible protein LPS Lipopolysaccharide LVFX Levofloxacin MCP-1 Monocyte chemoattractant protein-1 MIP-1α Macrophage inflammatory protein-1α MIP-1β Macrophage inflammatory protein-1β. Inflammatory cytokines lower the blood pressure via blood vessels dilation and blood clotting within the capillaries of organs. These effects can aid the immune system in fighting infection, but can be harmful. Drugs that are effective against bacterial infections and reduce inflammatory cytokines are required to avoid such harmful effects Treatment with such drugs may help prevent septic shock and reduce mortality. Some antibiotics such as tetracycline3,4, macrolide[5,6,7] and oxazolidinone[8,9] have effectively reduced the production of inflammatory cytokines. STFX was effective against Haemophilus influenzae pneumonia in a murine m odel[14]
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