CP-115,953 stimulates cytokine production by lymphocytes

Abstract

The cytotoxic quinolone CP-115,953 specifically exerts its inhibitory effect upon eukaryotic topoisomerase II. CP-115,953 stimulates DNA cleavage mediated by topoisomerase II with a potency approximately 600 times greater than that of ciprofloxacin, a quinolone antibacterial agent that currently is in clinical use. Because ciprofloxacin has been reported to strongly enhance interleukin-2 production, we considered it important to study the effect of CP-115,953 on interleukin-2 and gamma interferon (IFN-␥) mRNA and protein expression in mitogen-stimulated human peripheral blood lymphocytes. For comparison, novobiocin and the antineoplastic drug etoposide were also included in the study. CP-115,953 (25 M) enhanced interleukin-2 mRNA levels up to 8-fold and IFN-␥ mRNA concentrations up to 6.5-fold. In contrast, ciprofloxacin (282 M) induced mRNAs for interleukin-2 and IFN-␥ up to 20-fold and 7.8-fold, respectively. However, CP-115,953 showed more prolonged kinetics of IFN-␥ mRNA production than ciprofloxacin. At high concentrations (Ն141 M), ciprofloxacin was a greater inducer of interleukin-2 production and exhibited a higher level of stimulatory action than CP-115,953 on IFN-␥ synthesis. At low concentrations, however, CP-115,953 (Յ25 M) was more potent than ciprofloxacin in inducing interleukin-2 and IFN-␥ synthesis. Etoposide or novobiocin did not influence cytokine mRNA expression. Thus, among the topoisomerase II inhibitors tested, fluoroquinolones are unique in stimulating cytokine synthesis in lymphocyte cultures.DNA topoisomerases are a class of enzymes that primarily alter DNA conformation through a concerted breaking and rejoining of DNA strands, thereby controlling the topological state of DNA (3, 4, 49). Topoisomerase II is not only crucially involved in DNA replication but also participates in transcription, DNA repair, and recombination (18). Nucleotide sequencing of genes encoding the topoisomerase enzymes from eukaryotic and prokaryotic cells shows all type II topoisomerases to be structurally and phylogenetically related. Eukaryotic DNA topoisomerase II corresponds to the bacterial DNA gyrase and is a ubiquitous ATP-dependent type II topoisomerase (4). Eukaryotic topoisomerase II is the primary cellular target for several clinically important antitumor agents (e.g., etoposide) (7, 46), while the prokaryotic counterpart is the target for fluoroquinolone antibacterial drugs (24).The lethal target of fluoroquinolone antibiotics in bacteria is the association between DNA and DNA gyrase (24, 34). Fluoroquinolones in clinical use have, in general, been found to be only weak inhibitors of the eukaryotic topoisomerase II in in vitro assays exploring relaxation or catenation of supercoiled double-stranded DNA (19,25,26). However, a number of new fluoroquinolone derivatives with enhanced activity against eukaryotic topoisomerase II exhibited by their strong inhibitory effects on eukaryotic DNA replication have been characterized, and their structure-activity relationships have been determined (3,9,12,13,17,1...

Cellular and humoral immunodepression in vultures feeding upon medicated livestock carrion

“…The observed low levels of T cells and cytokines associated with the presence of antibiotics seem to adjust to the previously mentioned feedback pattern. Thus, low levels of T lymphocytes can secrete low levels of cytokines and chemotactic molecules which may be low enough to contribute to their feedback participation promoting the presence of T lymphocytes (Jiménez-Valera et al 1995;Riesbeck & Forsgren 1995;Campello et al 2006).…”

Immunomodulating effect of antimicrobial agents on cytokine production by human polymorphonuclear neutrophils

“…During the course of infection, cytokines have been recognised as capable of modifying cell activities. IL-8, IL-1␤, TNF-␣ and IL-6, which have a broad spectrum of activity on cells involved in immune and inflammatory reactions [10], could help to mediate resistance to bacterial pathogens. For example, IL-1␤ and TNF-␣ induce the adherence of PMNs, lymphocytes and monocytes to the endothelial cells and limit infection allowing the passage of these cells into the inflammatory sites [10].…”

“…IL-8, IL-1␤, TNF-␣ and IL-6, which have a broad spectrum of activity on cells involved in immune and inflammatory reactions [10], could help to mediate resistance to bacterial pathogens. For example, IL-1␤ and TNF-␣ induce the adherence of PMNs, lymphocytes and monocytes to the endothelial cells and limit infection allowing the passage of these cells into the inflammatory sites [10]. Recent investigations have shown that some antibiotics, in addition to their antimicrobial effects, can interfere with cytokine production.…”

“…Recent investigations have shown that some antibiotics, in addition to their antimicrobial effects, can interfere with cytokine production. Some inhibit the synthesis of IL-1, TNF-␣ and IL-6 in LPS-stimulated human monocyte cultures [11][12][13][14], others induce an enhancement of IL-2 and interferon ␥ (IFN-␥) release in lymphocyte cultures [10]. Some increase mRNA levels of cytokines, such as IL-1␤, IL-3, IL-4, IL-6, TNF-␣, granulocyte-macrophage colony-stimulating factor (GM-CSF) and lymphotoxin [10,11,15].…”

“…Some inhibit the synthesis of IL-1, TNF-␣ and IL-6 in LPS-stimulated human monocyte cultures [11][12][13][14], others induce an enhancement of IL-2 and interferon ␥ (IFN-␥) release in lymphocyte cultures [10]. Some increase mRNA levels of cytokines, such as IL-1␤, IL-3, IL-4, IL-6, TNF-␣, granulocyte-macrophage colony-stimulating factor (GM-CSF) and lymphotoxin [10,11,15]. In a recent study, Mattsson et al [16] demonstrated that ␤-lactam antibiotics, macrolides, vancomycin or clindamycin themselves did not induce TNF-␣ release, while other authors have described that the quinolones trovafloxacin and grepafloxacin and the macrolide clarithromycin were capable of inhibiting the in vitro production of IL-1␣, IL-1␤, TNF-␣, IL-6 and IL-8 by human monocytes [17][18][19].…”