TUMOR-NECROSIS-FACTOR AND ASSOCIATED CYTOKINES IN THE HOSTS RESPONSE TO MALARIA

Tumour Necrosis Factor (TNF) is produced at the initiation of malaria infections (re-erythrocytic phase), as demonstrated by the release of bioactive TNF by peripheral blood mononuclear cells from individuals r esiding in endemic areas after stimulation with stage specific sporozo ite antigens. During the erythrocytic phase, TNF production is greatly augmented by parasite antigens at the time of schizont rupture and me rozoite release from infected erythrocytes. Some of the strongest indu cers of TNF synthesis and release are malaria toxins, e.g. glycosylpho sphatidylinositol 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. T hough earlier reports of the capability of serum containing TNF to kil l plasmodia supported this idea, later experiments with recombinant TN F 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 other cytokines, s uch as interleukin (IL)-1, IL-6, IL-12, interferon-gamma (IFN gamma) a s well as nitric oxide intermediates (NOI) and reactive oxygen interme diates (ROI). This positioned TNF as a key regulator of the immune res ponse 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, bleedi ng and reversible coma of severe malaria seen in approximately 1 perce nt of individuals with malaria. Therein lies the rub; factors importan t in the control of malaria also appear to have detrimental properties . Research presented in this review characterizes TNF and associated c ytokines' importance in the immune response to malaria.