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Gene Expression by a Nonlysosomotropic Mechanism1
Department of Microbiology, Evans Memorial Department of Clinical Research, and Department of Medicine, Boston University School of Medicine, Boston, MA 02118
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-
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-
release from human PBMC at therapeutically attainable concentrations.
Additional studies to determine the specificity of this effect showed
that although CQ reduced IL-1ß and IL-6 release, secretion of RANTES
was unaffected. CQ acted by reducing TNF- mRNA accumulation without
destabilizing its mRNA or interfering with NF-
B nuclear
translocation or p50/p65 isoform composition of DNA-binding complexes.
Intracellular cytokine staining indicated that CQ reduced TNF-
production pretranslationally without interfering with TNF-
processing or release. We utilized bafilomycin A1
pretreatment to block the pH-dependent trapping of CQ in endosomes and
lysosomes. Although bafilomycin A1 alone did not interfere
with TNF- expression, preincubation augmented the ability of CQ to
reduce TNF- mRNA levels, suggesting that CQ did not act by a
lysosomotropic mechanism. Using confocal microscopy, we showed that
bafilomycin A1 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- gene expression without altering translocation of
NF-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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