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薬理と治療
Abstract
Objective The present study was carried out to examine the influence of clarithromycin(CAM)and its metabolites, M−1, M−4 and M−5 on interleukin(IL)−8 production in humanbronchial epithelial cells, BEAS−2B cells, in response to tumor necrosis factor(TNF)−αstimulation in vitro.Methods BEAS−2B cells(5×105 cells/mL)were stimulated with 5.0 ng/mL TNF−α in thepresence of various concentrations of either CAM, M−1, M−4 or M−5. The culture supernatantswere collected 24 hours after the start of cell culture, and IL−8 levels in the culturesupernatants were assayed by ELISA. We also examined IL−8 mRNA expression and nuclearfactor(NF)−κB activation in BEAS−2B cells by RT−PCR and ELISA, respectively.Results The addition of CAM at more than 0.4μg/mL was significantly suppressed the productionof IL−8 in BEAS−2B cells, when the agent was added 2 hours before(but not after)the start of TNF−α stimulation. Pretreatment of cells with M−4 and M−5, but not M−1,could also inhibit the production of IL−8. The minimum concentration of these agents, whichcaused a significant suppression was 0.04μg/mL and 0.1μg/mL, respectively. Further more,M−4 at more than 0.1μg/mL could suppress the ability of cells to produce IL−8 induced byTNF−α stimulation, even when the treatment of cells with agent was started 2 hours afterTNF−α stimulation. We then examined the influence of M−4 on NF−κB activation and IL−8mRNA expression in 2 hour−treated BEAS−2B cells. The addition of M−4 into cell culturecaused a significant suppression of NF−κB activation and IL−8 mRNA expression, when thecells were treated with the agent at 0.04μg/mL.Conclusion These results strongly suggest that metabolized materials of CAM, especiallyM−4 could suppress the IL−8 production through the inhibition of NF−κB activation and IL−8 mRNA expression, which were increased by TNF−α stimulation.(Jpn Pharmacol Ther 2008;36:1097−104)KEY WORDS Clarithromycin, Metabolized clarithromycin, Epithelial cells, IL−8, Suppression,in vitro
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