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 alpha. The tumor necrosis factor alpha 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 alpha 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 alpha production was measured in supernatants by enzyme-linked immunosorbent assay. The psoriasis-associated tumor necrosis factor alpha promoter allele TNF238.2 showed a significantly decreased transcriptional activity. Peripheral blood mononuclear cells carrying this allele produced significantly less tumor necrosis factor alpha after stimulation with T cell mitogens and streptococcal antigens in comparison to controls. The promoter allele TNF238.2 seems to influence tumor necrosis factor alpha production; a possible role in the pathogenesis of psoriasis has to be further evaluated.

Family-based analysis of tumor necrosis factor and lymphotoxin-α tag polymorphisms with type 1 diabetes in the population of South Croatia

“…However, the South Croatian families analyzed in this study have not been HLA typed and therefore we can not determine whether the effects of the TNF/LTA variants are primary or secondary to HLA loci. A functional support for independent effects may be explained by transcription rate enhancement of TNF gene by TNF promoter −308 and −238 SNPs, functional control of TNF promoter SNPs on LTA expression and expression of other nearby genes [34,35,[37][38][39]. An integrated role of TNF and other inflammatory cytokines in the destruction of pancreatic beta cells [19] provides further argument for a TNF/LTA T1DM effect.…”

“…Interestingly, overtransmission of A-G rs1800629(G-308A)-rs361525(G-238A) haplotype shows stronger significance (2.384×10 −5 ) than any of the single markers individually (rs1800629 (G-308A), p = 1.2×10 4 ; rs361525(G-238A), p = 8.15×0 −3 ). As both promoter polymorphisms have been associated with transcriptional enhancement rate it is possible that when acting in cis these two markers show an even stronger interaction [33][34][35].…”

Tumor Necrosis Factor-α Gene Polymorphisms and Risk of Oral Cancer: Evidence from a Meta-analysis

“…Kaluza et al (2000) reported that the TNF-α-238 G allele caused a significant increase in the transcription of the TNF-α gene in human T and B cells. Thus, the effect of the TNF-α-238G allele against cancer may be conferred by an increase in TNF-α production.…”

“…TNF-α gene is located on chromosome 6p21.231 in the polymorphic region of MHC III, and its promoter polymorphisms have been intensively studied as a potential determinant of disease susceptibility (Kaluza et al, 2000;Gupta et al, 2008). There is also an increasing evidence that TNF-α may promote the development and spread of cancer (Liu et al, 2005;Hohberger et al, 2008;Liu et al, 2012b).…”

“…There is also an increasing evidence that TNF-α may promote the development and spread of cancer (Liu et al, 2005;Hohberger et al, 2008;Liu et al, 2012b). Commonly described variants of TNF-α gene polymorphisms consist of G to A transitions in the promoter region at positions _238 and _308 (Kaluza et al, 2000). So far, TNF-α promoter polymorphism has been related to numerous cancers, such as bladder cancer (Marsh et al, 2003), renal cell carcinoma (Nakajima et al, 2001), non-small cell lung carcinoma (Shih et al, 2006) cervical cancer (Govan et al, 2006;Liu et al, 2012b) and breast carcinoma (Mestiri et al, 2001).…”