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Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes.
Rheumatology (Oxford). 2006 Jun; 45(6):703-10.R

Abstract

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-1beta 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-1beta and IL-6 release was accompanied by a decrease in their steady-state mRNA levels. The transcription rates of the IL-1beta and IL-6 genes were not changed by chloroquine, whereas the stability of IL-1beta 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-1beta and IL-6.

CONCLUSIONS

Our results indicate that chloroquine-mediated inhibition of TNF-alpha, IL-1beta 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-1beta and IL-6 mRNA, at least in part, by decreasing their stability and by a pH-dependent mechanism.

Authors+Show Affiliations

Department of Biochemistry, College of Medicine, Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 137-701, South Korea.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16418198

Citation

Jang, C-H, et al. "Chloroquine Inhibits Production of TNF-alpha, IL-1beta and IL-6 From Lipopolysaccharide-stimulated Human Monocytes/macrophages By Different Modes." Rheumatology (Oxford, England), vol. 45, no. 6, 2006, pp. 703-10.
Jang CH, Choi JH, Byun MS, et al. Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. Rheumatology (Oxford). 2006;45(6):703-10.
Jang, C. H., Choi, J. H., Byun, M. S., & Jue, D. M. (2006). Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. Rheumatology (Oxford, England), 45(6), 703-10.
Jang CH, et al. Chloroquine Inhibits Production of TNF-alpha, IL-1beta and IL-6 From Lipopolysaccharide-stimulated Human Monocytes/macrophages By Different Modes. Rheumatology (Oxford). 2006;45(6):703-10. PubMed PMID: 16418198.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chloroquine inhibits production of TNF-alpha, IL-1beta and IL-6 from lipopolysaccharide-stimulated human monocytes/macrophages by different modes. AU - Jang,C-H, AU - Choi,J-H, AU - Byun,M-S, AU - Jue,D-M, Y1 - 2006/01/17/ PY - 2006/1/19/pubmed PY - 2006/8/5/medline PY - 2006/1/19/entrez SP - 703 EP - 10 JF - Rheumatology (Oxford, England) JO - Rheumatology (Oxford) VL - 45 IS - 6 N2 - 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-1beta 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-1beta and IL-6 release was accompanied by a decrease in their steady-state mRNA levels. The transcription rates of the IL-1beta and IL-6 genes were not changed by chloroquine, whereas the stability of IL-1beta 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-1beta and IL-6. CONCLUSIONS: Our results indicate that chloroquine-mediated inhibition of TNF-alpha, IL-1beta 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-1beta and IL-6 mRNA, at least in part, by decreasing their stability and by a pH-dependent mechanism. SN - 1462-0324 UR - https://www.unboundmedicine.com/medline/citation/16418198/Chloroquine_inhibits_production_of_TNF_alpha_IL_1beta_and_IL_6_from_lipopolysaccharide_stimulated_human_monocytes/macrophages_by_different_modes_ L2 - https://academic.oup.com/rheumatology/article-lookup/doi/10.1093/rheumatology/kei282 DB - PRIME DP - Unbound Medicine ER -