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

Abstract

Genes encoded on chromosome 6 within the major histocompatibility complex region are thought to play an important role in the pathogenesis of psoriasis. A potential candidate gene is tumor necrosis factor α. The tumor necrosis factor α promoter contains several polymorphisms including two G→A transitions at position -308 and -238, which are the most common in Caucasian populations. The TNF238.2 (-238A) allele has been strongly associated with psoriasis. We have investigated the effect of the -238 and -308 variants on transcription of the tumor necrosis factor α gene in luciferase reporter gene assays. In addition, peripheral blood mononuclear cells of 47 patients with psoriasis and 43 controls were stimulated with different antigens and mitogens (streptococcal sonicate and superantigen, lipopolysaccharide, phorbol-12-myristate, phytohemagglutinin, CD3 antibodies) and tumor necrosis factor a production was measured in supernatants by enzyme-linked immunosorbent assay. The psoriasis-associated tumor necrosis factor α promoter allele TNF238.2 showed a significantly decreased transcriptional activity. Peripheral blood mononuclear cells carrying this allele produced significantly less tumor necrosis factor a after stimulation with T cell mitogens and streptococcal antigens in comparison to controls. The promoter allele TNF238.2 seems to influence tumor necrosis factor α production; a possible role in the pathogenesis of psoriasis has to be further evaluated. © 2000 Elsevier Science B.V.