Many articles quoted in this review originate from the authors' files; others were chosen from searches on Pubmed on the combination of the words “fluoroquinolones”, “quinolones”, or specific quinolone names with each of the following terms: “immunity”, “immune modulation”, “immunomodulation”, “immune system”, “immunology”, “immunoglobulines”, “immune suppression”, “immune compromised hosts”, “nuclear factors”, “signal transduction”, “gene transcription”, “NFkB”, “IkB”, “IKK”, “MAPK”,
ReviewImmunomodulatory effects of quinolones
Section snippets
Quinolones and prokaryotic or eukaryotic topoisomerases
When the first fluoroquinolones—eg, norfloxacin, ofloxacin, and ciprofloxacin—were about to be launched onto the market, one of the main issues was to exclude any mutagenic or genotoxic potential. Since fluoroquinolones inhibit bacterial DNA gyrase and topoisomerase IV,23, 52, 53 the mammalian topoisomerase type II enzymes could in principle also be inhibited by fluoroquinolones. The selectivity of fluoroquinolones for bacterial topoisomerases is up to 1000-fold that of mammalian counterparts.54
In vitro experiments
Results summarised in table 1 complete the synopsis of data provided by Riesbeck20 and Labro.18 Since the publication of these comprehensive reviews summarising published data up to the years 2000/2001, only a few publications have described the in-vitro effects of recently launched fluoroquinolones on cytokine synthesis by lipopolysaccharide-stimulated human monocytes; ciprofloxacin serves as a reference, despite the high drug concentrations originally studied.
Ciprofloxacin decreased cytokine
Ex vivo studies
Based on the findings described above 44, 47, 73 the in-vivo effect of orally administered ciprofloxacin (25 mg/kg) on the capacity of PBMC from healthy human volunteers to produce interleukin 1α, interleukin 1β, interleukin 6, and TNFα ex vivo in response to endotoxin stimulation was established.46
Eight patients received ciprofloxacin (25 mg/kg) orally twice a day for 7 days corresponding to usual treatment. Peripheral blood was collected the day before the treatment (DO), 2 hours after the
Intra-abdominal infections
Assessment of the effects of ciprofloxacin and rufloxacin in an intra-abdominal infection model represents one of the first attempts to establish whether fluoroquinolones in vivo alter the T-cell response and cytokine production.61 These two fluoroquinolones were studied because they are inactive against Bacteroides fragilis in vitro, so that their in-vivo efficacy is most probably because immunomodulatory effects.78
The elimination of B fragilis from 66·6–63·5% of treated animals coincided with
Mechanisms of immunomodulatory activity
The first findings on potential immunomodulating activity of fluoroquinolones were published in the late 1980s.27, 44, 124, 125 Whereas the mechanism of antibacterial activity of fluoroquinolones and their effects on topoisomerase II in prokaryotic and eukaryotic cells have been broadly investigated in vitro and in vivo,126 the basic mechanisms underlying their immunomodulatory activity have not been elucidated in a comprehensive and satisfying manner. The sequence of events after penetration
Conclusion
Progress has been made in elucidating some of the specific mechanisms underlying the immunomodulatory effects of quinolones. The kinetics of cytokine and chemokine production, the elucidation of early gene transcription by analysis of cytokines mRNAs, as well as the activation or inhibition of certain key transcription factors within mammalian cells by quinolones have all contributed to a better understanding of their unique effects. Nevertheless, the exact sequence of events following
Search strategy and selection criteria
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Antibiotics and phagocytosis
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Immunomodulating activity of quinolones: review
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Effect of ciprofloxacin on the activation of the transcription factors nuclear factor κ B, mathfrak, activator protein-I and nuclear factor-interleukin-6, and interleukin-6 and interleukin-8 mRNA expression in a human endothelial cell line
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Effect of trovafloxacin on production of cytokines by human monocytes
Antimicrob Agents Chemother
Protection against lipopolysaccharide-induced death by fluoroquinolones
Antimicrob Agents Chemother
Effect of ciprofloxacin on lethal and sublethal challenge with endotoxin and on early cytokine response in a murine in vivo model
J Antimicrob Chemother
Immunomodulatory effects of moxifloxacin in comparison to ciprofloxacin and G-CSF in a murine model of cyclophosphamide-induced leukopenia
Eur J Haematol
The immunomodulating activities of antibacterials
Exp Opin Invest Drugs
Pharmacokinetics of selected antibacterial agents
Pharmacokinetics of the quinolone antimicrobial agents
Evidence that the antibiotic ciprofloxacin counteracts cyclosporine-dependent suppression of cytokine production
Transplantation
Ciprofloxacin induces an immunomodulatory stress response in human T lymphocytes
Antimicrob Agents Chemother
Superinduction of cytokine gene transcription by ciprofloxacin
J Immunol
Comparative effects of quinolones on human mononuclear leucocyte functions
J Antimicrob Chemother
Ciprofloxacin treatment in vivo increases the ex vivo capacity of lipopolysaccharide-stimulated human monocytes to produce Il-1, Il-6 and tumor-necrosis factor alpha
Clin Exp Immunol
Interleukin-1 production by antibiotic treated human monocytes
J Antimicrob Chemother
In vitro and in vivo effects of quinolones on monocyte cytokine production
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