A TH1-ASSOCIATED INCREASE IN TUMOR-NECROSIS-FACTOR-ALPHA EXPRESSION IN THE SPLEEN CORRELATES WITH RESISTANCE TO BLOOD-STAGE MALARIA IN MICE

We investigated the kinetics of tissue-specific mRNA expression and sy stemic production of tumor necrosis factor alpha (TNF-alpha) and the k inetics of splenic expression of mRNAs of gamma interferon (IFN-gamma) and interleukin-4 (IL-4), cytokines that may regulate TNF-alpha produ ction, during the early phase of blood-stage infection with Plasmodium chabaudi AS. Northern blot analysis revealed that resistant C57BL/6 m ice, which clear the infection by 4 weeks, had higher levels of TNF-al pha mRNA in the spleen and liver early during infection than did susce ptible A/J mice, which succumb to the disease 10 days after initiation of infection. Treatment of resistant mice with a polyclonal anti-TNF- alpha antibody confirmed the protective role of TNF-alpha early during the course of infection. Furthermore, resistant C57BL/6 mice also exp ressed high levels of mRNA of IFN-gamma (a Th1 marker) and low levels of mRNA of IL-4 (a Th2 marker) in the spleen, whereas susceptible A/J mice had low levels of IFN-gamma mRNA but high levels of IL-4 mRNA in the spleen early during infection. On the other hand, susceptible A/J mice expressed high levels of TNF-alpha mRNA in the liver and had high levels of TNF-alpha protein in serum, as measured by enzyme-linked im munosorbent assay, later during infection just before death occurred. These results demonstrate that a Th1-associated increase in TNF-alpha mRNA expression in the spleen early during infection correlates with r esistance to P. chabaudi AS, whereas increased TNF-alpha mRNA levels i n the liver and excessive levels of the TNF-alpha protein in serum lat er during infection correlate with susceptibility. Thus, the role of T NF-alpha during malaria appears to depend on the timing and site of it s expression and the presence of cytokines regulating its production.