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 blunt s lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha releas e, it was hypothesized that this drug would also interfere with the inflamm atory response to C. neoformans and Candida albicans, another fungal opport unist. CQ inhibited TNF-alpha release from peripheral blood mononuclear cel ls from healthy and human immunodeficiency virus-positive donors without af fecting NF-kappaB activation. CQ reduced TNF-alpha mRNA levels by a pH-depe ndent mechanism in a manner similar to 2 unrelated alkalizing drugs (ammoni um chloride and bafilomycin), which also inhibited TNF-alpha gene expressio n. Although CQ inhibited release of interleukin (IL)-1 beta and IL-6, it di d not affect IL-10 or macrophage inflammatory protein-1 alpha production. T hus, 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 re lease and suggests that the mechanism of CQ's anti-inflammatory effects is stimulus specific.