Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism

Genes encoded on chromosome 6 within the major histocompatibility complex r egion are thought to play an important role in the pathogenesis of psoriasi s. A potential candidate gene is tumor necrosis factor alpha. The tumor nec rosis factor alpha promoter contains several polymorphisms including two G- ->A transitions at position -308 and -238, which are the most common in Cau casian populations. The TNF238.2 (-238A) allele has been strongly associate d with psoriasis. We have investigated the effect of the -238 and -308 vari ants on transcription of the tumor necrosis factor alpha gene in luciferase reporter gene assays. In addition, peripheral blood mononuclear cells of 4 7 patients with psoriasis and 43 controls were stimulated with different an tigens and mitogens (streptococcal sonicate and superantigen, lipopolysacch aride, phorbol-12-myristate, phytohemagglutinin, CD3 antibodies) and tumor necrosis factor alpha production was measured in supernatants by enzyme-lin ked immunosorbent assay. The psoriasis-associated tumor necrosis factor alp ha promoter allele TNF238.2 showed a significantly decreased transcriptiona l activity. Peripheral blood mononuclear cells carrying this allele produce d significantly less tumor necrosis factor alpha after stimulation with T c ell mitogens and streptococcal antigens in comparison to controls. The prom oter allele TNF238.2 seems to influence tumor necrosis factor alpha product ion; a possible role in the pathogenesis of psoriasis has to be further eva luated.