期刊
RHEUMATOLOGY
卷 45, 期 6, 页码 703-710出版社
OXFORD UNIV PRESS
DOI: 10.1093/rheumatology/kei282
关键词
chloroquine; rheumatoid arthritis; cytokines; gene regulation; monocytes/macrophages; inflammation
类别
Objectives. TNF-alpha, IL-1 and IL-6 are known to have primary roles in the pathogenesis of rheumatoid arthritis and other inflammatory diseases. The anti-rheumatic drug chloroquine has been shown to inhibit TNF-alpha, IL-1 and IL-6 production from mononuclear phagocytes. We examined the underlying mechanisms involved in the chloroquine-induced inhibition of cytokine production. Methods. Human peripheral blood mononuclear cells and monocytes/macrophages and monocytic U-937 and THP-1 cells were stimulated with lipopolysaccharide, and TNF-alpha, IL-1 beta and IL-6 production was measured by ELISA. Levels of mRNA were measured by northern blotting and reverse transcription-polymerase chain reaction. Synthesis of 26-kDa TNF-alpha precursor was measured by metabolic labelling and immunoprecipitation analysis. Transcription rate was determined by nuclear run-on assay. Results. TNF-alpha release from the cells was inhibited by chloroquine, whereas the steady-state level of TNF-alpha mRNA and synthesis of 26-kDa TNF-alpha precursor were not changed by chloroquine. In contrast, chloroquine-induced inhibition of IL-1 beta and IL-6 release was accompanied by a decrease in their steady-state mRNA levels. The transcription rates of the IL-1 beta and IL-6 genes were not changed by chloroquine, whereas the stability of IL-1 beta and IL-6 mRNA was decreased by chloroquine. Weak-base amines such as methylamine and ammonium chloride had no effect on the production of TNF-alpha, whereas they partially blocked the production of IL-1 beta and IL-6. Conclusions. Our results indicate that chloroquine-mediated inhibition of TNF-alpha, IL-1 beta and IL-6 synthesis occurs through different modes in lipopolysaccharide-stimulated human monocytes/macrophages: it blocks the conversion of cell-associated TNF-alpha precursor to mature soluble protein, whereas it reduces the levels of IL-1 beta and IL-6 mRNA, at least in part, by decreasing their stability and by a pH-dependent mechanism.
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