Tumour necrosis factor and associated cytokines in the host's response to malaria

Tumour Necrosis Factor (TNF) is produced at the initiation of malaria infections (pre-erythrocytic phase), as demonstrated by the release of bioactive TNF by peripheral blood mononuclear cells from individuals residing in endemic areas after stimulation with stage specific sporozoite antigens. During the erythrocytic phase, TNF production is greatly augmented by parasite antigens at the time of schizont rupture and merozoite release from infected erythrocytes. Some of the strongest inducers of TNF synthesis and release are malaria toxins, e.g. glycosylphosphatidylinositol moieties and malaria pigment. Because of TNF's well-known cytotoxic activity it was originally hypothesized that it alone was responsible for killing parasites directly or within host cells. Though earlier reports of the capability of serum containing TNF to kill plasmodia supported this idea, later experiments with recombinant TNF showed a lack of significant parasiticidal activity. Recent studies investigating related factors showed that they were involved with TNF in the control of infection. These factors included -ther cytokines, such as interleukin (IL)-1, IL-6, IL-12, interferon-gamma (IFN gamma) as well as nitric oxide intermediates (NOI) and reactive oxygen intermediates (ROI). This positioned TNF as a key regulator of the immune response against the malaria parasite. However, it must be noted that TNF and its associated factors are also responsible for the fever, aches and pains of acute illness, as well as the hypoglycemia, shock, bleeding and reversible coma of severe malaria seen in approximately 1 percent of individuals with malaria. Therein lies the rub; factors important in the control of malaria also appear to have detrimental properties. Research presented in this review characterizes TNF and associated cytokines' importance in the immune response to malaria.