Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-ΚB transcription factors

Tohru Kikuchi, Koichi Hagiwara, Yoshihiro Honda, Kazunori Gomi, Takao Kobayashi, Hiroshi Takahashi, Yutaka Tokue, Akira Watanabe, Toshihiro Nukiwa

    Research output: Contribution to journalArticlepeer-review

    172 Citations (Scopus)

    Abstract

    Erythromycin and other macrolides are effective for the treatment of chronic inflammatory airway diseases such as diffuse panbronchiolitis (DPB) and chronic sinusitis. The effect of macrolides in DPB is suggested to be anti-inflammatory rather than antibacterial. We investigated the effects of clarithromycin on interleukin-8 (IL-8) production using human peripheral monocytes and the human monocytic leukaemia cell line, THP-1. Bacterial extracts from Escherichia coli, Pseudomonas aeruginosa and Helicobacter pylori, as well as E. coli-derived lipopolysaccharide (LPS), induced IL-8 production. Clarithromycin suppressed this production in a dose-dependent manner in both monocytes and THP-1 cells (49.3-75.0% inhibition at 10 mg/L). A luciferase reporter gene assay with plasmids containing a serially deleted IL-8 promoter fragment showed that both the activator protein-1 (AP-1) and/or the nuclear factor-κB (NF-κB) binding sequences were responsible for the LPS and clarithromycin responsiveness of the IL-8 promoter. Consistently, in an electromobility shift assay, LPS increased the specific binding of both AP-1 and NF-κB, whereas clarithromycin suppressed it. Moreover, LPS and clarithromycin regulated three other promoters that have either the NF-κB or the AP-1 binding sequences: two synthetic (pAP-1-Luc and pNF-κB-Luc) and one naturally occurring (ELAM-Luc). Our results indicate that clarithromycin modified inflammation by suppressing IL-8 production and that clarithromycin may affect the expression of other genes through AP-1 and NF-κB. In addition to treatment of airway diseases, the anti-inflammatory effect of macrolides may be beneficial for the treatment of other inflammatory diseases such as chronic gastritis caused by H. pylori.

    Original languageEnglish
    Pages (from-to)745-755
    Number of pages11
    JournalJournal of Antimicrobial Chemotherapy
    Volume49
    Issue number5
    Publication statusPublished - 2002

    ASJC Scopus subject areas

    • Pharmacology
    • Microbiology (medical)
    • Infectious Diseases
    • Pharmacology (medical)

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