There is now considerable evidence that
cerebral malaria may be related to the over-production of tumour
necrosis factor (TNF). Nevertheless, our knowledge is very poor concerning the
biological events which lead up to this TNF over-production. Furthermore,
interleukin-6 (IL-6) is produced in large amounts during
malaria infection and seems to have inhibitory action on TNF production.
Anti-malarial drugs were investigated for their ability to interfere with TNF and
IL-6 secretion by human non-immune macrophages stimulated by
lipopolysaccharides (LPS) or Plasmodium falciparum culture supernatant. Macrophages were pretreated with
chloroquine,
quinine,
proguanil,
mefloquine or
halofantrine before stimulation. TNF and
IL-6 production were suppressed in a dose-dependent manner when macrophages were treated with
chloroquine, but not with other
anti-malarial drugs. Considering that
chloroquine probably acts via lysosomotropic mechanisms, and that
iron metabolism may interfere with the non-specific immune response, we focused our attention on these biochemical events in order to investigate the mechanisms by which
chloroquine inhibits
cytokine production. Our results demonstrated that
chloroquine-induced inhibition of TNF and
IL-6 production is not mediated through a lysosomotropic mechanism, and that
chloroquine probably acts on TNF secretion by disrupting
iron homeostasis. Inhibition of
IL-6 production seems not to be mediated through these pathways. These observations suggest that
chloroquine may help to prevent
cerebral malaria whatever the
drug sensitivity of the parasite strain, and may provide new tools for an anti-disease
therapy regardless of the emergence of parasite multi-drug resistance.