The tumor necrosis factor-alpha protein level and caspase activity, which is related to CM pathogenesis, was significantly reduced in the minocycline-treated group.
Children presenting with acute CM had significantly higher concentrations of TNF-α (<i>P</i> < 0.001), interferon gamma (IFN-γ) (<i>P</i> = 0.0019), IL-2 (<i>P</i> = 0.0004), IL-6 (<i>P</i> < 0.001), IL-8 (<i>P</i> < 0.001), and IL-10 (<i>P</i> < 0.001) in sera than healthy controls.
Further tests for association with severe malaria using genotype models controlling for age, parasitaemia and HbAS showed a significant association of the TNF-238 polymorphism with susceptibility to severe malaria (95% CI=1.43-6.02, OR=2.94, p=0.003237) The GG genotype of TNF-238 significantly increased the risk of developing cerebral malaria from asymptomatic malaria and uncomplicated malaria (95% CI=1.99-18.17, OR=6.02, p<0.001 and 95% CI=1.78-8.23, OR=3.84, p<0.001 respectively).
Up-regulated TNF-α expression has also been found in various neurodegenerative diseases such as cerebral malaria, AIDS dementia, Alzheimer's disease, multiple sclerosis, and stroke, suggesting a potential pathogenic role of TNF-α in these diseases as well.
Previous studies indicate that tumour necrosis factor (TNF) and lymphotoxin alpha (LTα) may be important for the development of cerebral malaria (CM) and other SM syndromes.
The frequency of the TNF U04 allele designated -1031C, -863C, and -857C was found to be significantly greater in patients with cerebral malaria than in patients with mild malaria (12.6%, cerebral malaria vs 5.6%, mild malaria; odds ratio =2.5; P=0.002).
The frequency of the TNF U04 allele designated -1031C, -863C, and -857C was found to be significantly greater in patients with cerebral malaria than in patients with mild malaria (12.6%, cerebral malaria vs 5.6%, mild malaria; odds ratio =2.5; P=0.002).
The hypothesis that tumor necrosis factor (TNF) aggravates malaria in children is supported by observations that TNF polymorphisms and high TNF levels have been associated with cerebral malaria.
TNFalpha receptors are upregulated in CM, with TNF receptor 2 (TNFR2) showing a higher upregulation than TNFR1 in vivo; (iv). in murine CM, low doses of TNFalpha seem to protect from CM, whereas excess TNFalpha induces CM and anti-TNFalpha therapies (antibodies, pentoxifylline) did not show any efficiency in protection from CM.
This report of RT-PCR on postmortem human tissues infected with CM demonstrates induction of the proinflammatory cytokines TNF-alpha and IL-1beta in the brain.
The OCT-1-binding genotype, found in approximately 5% of Africans, is associated with fourfold increased susceptibility to cerebral malaria in large case-control studies of West African and East African populations, after correction for other known TNF polymorphisms and linked HLA alleles.
In a large case-control study in Gambian children we find that homozygotes for the TNF2 allele, a variant of the TNF-alpha gene promoter region, have a relative risk of 7 for death or severe neurological sequelae due to cerebral malaria.