Chloroquine antagonizes the proinflammatory cytokine response to opportunistic fungi by alkalizing the fungal phagolysosome.
Recent observations demonstrated that the antimalarial drug chloroquine (CQ) can kill the opportunistic fungus Cryptococcus neoformans. Since CQ blunts lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha release, it was hypothesized that this drug would also interfere with the inflammatory response to C. neoformans and Candida albicans, another fungal opportunist. CQ inhibited TNF-alpha release from peripheral blood mononuclear cells from healthy and human immunodeficiency virus-positive donors without affecting NF-kappaB activation. CQ reduced TNF-alpha mRNA levels by a pH-dependent mechanism in a manner similar to 2 unrelated alkalizing drugs (ammonium chloride and bafilomycin), which also inhibited TNF-alpha gene expression. Although CQ inhibited release of interleukin (IL)-1beta and IL-6, it did not affect IL-10 or macrophage inflammatory protein-1alpha production. Thus, CQ interferes with fungus-induced TNF-alpha expression by a mechanism that probably depends on the alkalization of endolysosomes. This contrasts with CQ's reported pH-independent inhibition of LPS-stimulated TNF-alpha release and suggests that the mechanism of CQ's anti-inflammatory effects is stimulus specific.
Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts, USA.
S M
SM
Weber
S M
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Levitz
D021581:Active Transport, Cell Nucleus; D000643:Ammonium Chloride / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002176:Candida albicans / Q000276:immunology*; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D011992:Endosomes / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006679:HIV Seropositivity / Q000276:immunology*; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008247:Lysosomes / Q000187:drug effects*; D018942:Macrolides; D016328:NF-kappa B / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D000900:Anti-Bacterial Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D018942:Macrolides; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D000643:Ammonium Chloride; D002738:Chloroquine; C040929:bafilomycin A1