Chloroquine interferes with lipopolysaccharide-induced TNF-α gene expression by a nonlysosomotropic mechanism

被引:110
作者
Weber, SM
Levitz, SM
机构
[1] Boston Univ, Sch Med, Evans Mem Dept Clin Res, Dept Microbiol, Boston, MA 02118 USA
[2] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA
关键词
D O I
10.4049/jimmunol.165.3.1534
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Chloroquine (CQ) is a lysosomotropic weak base with over 60 years of clinical use for the treatment of malaria and rheumatologic disorders. Consistent with its anti-inflammatory properties, CQ has been shown to interfere with TNF-alpha release from mononuclear phagocytes. Because it is unclear how CQ mediates these immunomodulatory effects, we set out to elucidate its mechanism of action. CQ exhibited dose-dependent inhibition of LPS-induced TNF-alpha release from human PBMC at therapeutically attainable concentrations. Additional studies to determine the specificity of this effect showed that although CQ reduced IL-1 beta and IL-6 release, secretion of RANTES was unaffected. CQ acted by reducing TNF-alpha mRNA accumulation without destabilizing its mRNA or interfering with NF-kappa B nuclear translocation or p50/p65 isoform composition of DNA-binding complexes. Intracellular cytokine staining indicated that CQ reduced TNF-alpha production pretranslationally without interfering with TNF-alpha processing or release. We utilized bafilomycin A(1) pretreatment to block the pH-dependent trapping of CQ in endosomes and lysosomes. Although bafilomycin A(1) alone did not interfere with TNF-alpha expression, preincubation augmented the ability of CQ to reduce TNF-alpha mRNA levels, suggesting that CQ did not act by a lysosomotropic mechanism. Using confocal microscopy, we showed that bafilomycin A(1) pretreatment resulted in a dramatic redistribution of quinacrine, a fluorescent congener of CQ, from cytoplasmic vacuoles to the nucleus. These data indicate that CQ inhibits TNF-alpha gene expression without altering translocation of NF-kappa B p50/p65 heterodimers, This dose-dependent effect occurs over a pharmacologically relevant concentration range and does not require pH-dependent lysosomotropic accumulation of CQ.
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页码:1534 / 1540
页数:7
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