EFFECTS OF A POLYMORPHISM IN THE HUMAN TUMOR-NECROSIS-FACTOR-ALPHA PROMOTER ON TRANSCRIPTIONAL ACTIVATION

Tumor necrosis factor alpha (TNF alpha) is a potent immunomodulator an d proinflammatory cytokine that has been implicated in the pathogenesi s of autoimmune and infectious diseases. For example, plasma levels of TNF alpha are positively correlated with severity and mortality in ma laria and leishmaniasis, We have previously described a polymorphism a t -308 in the TNF alpha promoter and shown that the rare allele, TNF2, lies on the extended haplotype HLA-A1-B8-DR3-DQ2, which is associated with autoimmunity and high TNF alpha production, Homozygosity for TNF 2 carries a sevenfold increased risk of death from cerebral malaria, H ere we demonstrate, with reporter genes under the control of the two a llelic TNF promoters, that TNF2 is a much stronger transcriptional act ivator than the common allele (TNF1) in a human B cell line, Footprint analysis using DNase I and B cell nuclear extract showed the generati on of a hypersensitive site at -308 and an adjacent area of protection , There was no difference in affinity of the DNA-binding protein(s) be tween the two alleles, These results show that this polymorphism has d irect effects on TNF alpha gene regulation and may be responsible for the association of TNF2 with high TNF alpha phenotype and more severe disease in infections such as malaria and leishmaniasis.