We investigated the kinetics of tissue-specific mRNA expression and systemic production of tumor necrosis factor alpha (TNF-␣) and the kinetics of splenic expression of mRNAs of gamma interferon (IFN-␥) and interleukin-4 (IL-4), cytokines that may regulate TNF-␣ production, during the early phase of blood-stage infection with Plasmodium chabaudi AS. Northern blot analysis revealed that resistant C57BL/6 mice, which clear the infection by 4 weeks, had higher levels of TNF-␣ mRNA in the spleen

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... liver early during infection than did susceptible A/J mice, which succumb to the disease 10 days after initiation of infection. Treatment of resistant mice with a polyclonal anti-TNF-␣ antibody confirmed the protective role of TNF-␣ early during the course of infection. Furthermore, resistant C57BL/6 mice also expressed high levels of mRNA of IFN-␥ (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-␥ 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-␣ mRNA in the liver and had high levels of TNF-␣ protein in serum, as measured by enzyme-linked immunosorbent assay, later during infection just before death occurred. These results demonstrate that a Th1-associated increase in TNF-␣ mRNA expression in the spleen early during infection correlates with resistance to P. chabaudi AS, whereas increased TNF-␣ mRNA levels in the liver and excessive levels of the TNF-␣ protein in serum later during infection correlate with susceptibility. Thus, the role of TNF-␣ during malaria appears to depend on the timing and site of its expression and the presence of cytokines regulating its production.