Chloroquine antagonizes the proinflammatory cytokine response to opportunistic fungi by alkalizing the fungal phagolysosome

Abstract

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)-α 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-α release from peripheral blood mononuclear cells from healthy and human immunodeficiency virus-positive donors without affecting NF-κB activation. CQ reduced TNF-α mRNA levels by a pH-dependent mechanism in a manner similar to 2 unrelated alkalizing drugs (ammonium chloride and bafilomycin), which also inhibited TNF-α gene expression. Although CQ inhibited release of interleukin (IL)-1β and IL-6, it did not affect IL-10 or macrophage inflammatory protein-1α production. Thus, CQ interferes with fungus-induced TNF-α 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-α release and suggests that the mechanism of CQ's anti-inflammatory effects is stimulus specific.