Elsevier

Molecular Immunology

Volume 34, Issue 5, April 1997, Pages 391-399
Molecular Immunology

The −308 tumor necrosis factor-α promoter polymorphism effects transcription

https://doi.org/10.1016/S0161-5890(97)00052-7Get rights and content

Abstract

Since the tumor necrosis factor alpha (TNF-α) gene was found to be located in the central major histocompatibility complex (MHC) there has been much speculation concerning a genetic association between particular TNF alleles and disease susceptibility. A relationship between the MHC haplotype Al, B8, DR3, TNF-α expression levels and susceptibility to autoimmune disease has been suggested by several groups. The identification of the −308 polymorphism and its association with the HLA Al, B8, DR3 haplotype have led to speculation that the polymorphism may play a role in the altered expression of TNF-α. We have demonstrated that the region (−323 to −285) encompassing −308 in the TNF2 allele binds nuclear factors differently to the same region in the promoter of the more common TNF1 allele. The GA −308 polymorphism affected the affinity of factor binding and resulted in a factor binding to TNF2 but not TNF1. The observed differential binding was shown to be functional, with the 38 by region from TNF2 causing a two-fold greater activity of a heterologous promoter over that due to the same region in TNFI. To further substantiate the functional consequences of the TNF-α −308 polymorphism, we analysed both allelic forms of the TNF-α promoter region (−993 to +110) in a transient transfection assay, using luciferase as a reporter gene. The results showed that when present with the 3′UTR the −308A allelic form gave a two-fold greater level of transcription than the −308G form in PMA-stimulated Jurkat and U937 cells. This suggests that the −308 GA polymorphism may play a role in the altered TNF-α gene expression observed in individuals with the HLA Al, B8, DR3 haplotype.

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