In vivo and in vitro effects of fluoroquinolones on lipopolysaccharide-induced pro-inflammatory cytokine production

Abstract

Fluoroquinolones have been reported to affect cytokine production in vitro. We investigated the effects of fluoroquinolones on lipopolysaccharide (LPS)-induced inflammatory cytokine production in vivo and in vitro. LPS was administered to mice treated with ciprofloxacin, gatifloxacin, norfloxacin, and levofloxacin, and the serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta), and interleukin 6 (IL-6) were measured. In addition, peritoneal macrophages collected from mice were treated with the four fluoroquinolones for 1 h, followed by the addition of LPS, and the TNF-alpha, IL-1beta, and IL-6 levels in culture fluid were measured. In LPS-treated mice, ciprofloxacin, gatifloxacin, and norfloxacin (100 mg/kg) significantly reduced the serum TNF-alpha level (6.8%-63.6% of control). Levofloxacin at 100 mg/kg did not affect the TNF-alpha level, whereas levofloxacin at a lower dose (10 mg/kg) significantly increased the level. All four fluoroquinolones (100 mg/kg) investigated in this study tended to decrease the serum IL-1beta levels (65.5%-65.9% of control), but this was not a significant change. The serum IL-6 levels were increased in ciprofloxacin-administered mice, whereas the other fluoroquinolones did not affect the serum IL-6 levels. In mouse peritoneal macrophages, LPS induced TNF-alpha, IL-1beta, and IL-6 production. Ciprofloxacin, gatifloxacin, and norfloxacin (100 mug/ml) inhibited both TNF-alpha (12.1%-69.0% of control) and IL-1beta production (22.1%-68.8% of control). Levofloxacin (100 mug/ml) inhibited IL-1beta production (65.0% of control), but not TNF-alpha production. LPSstimulated IL-6 production was inhibited only by norfloxacin (59.5 % of control). Our in vivo and in vitro results suggest that fluoroquinolones, especially ciprofloxacin, gatifloxacin, and norfloxacin, which have a cyclopropyl group at the N1 position and/or a piperazinyl group at the C7 position, modify inflammatory responses.