The TNFa gene

The TNFa gene (Figure 1, about 3.6 kbp) is separated from that of lymphotoxin a (LTa, alternatively known as TNF(3) by 1.2 kbp within the major histocompatibility complex (MHC) locus on chromosome 6 between 6p21.1 and 6p21.3. The TNFa locus contains six microsatellites. Within the LTa (TNF(3)

gene there are three TNF-related polymorphisms: a Ncol RFLP polymorphism, named TNFB* I rare allele with less TNF-a production) in the presence of the restriction site and TNFB*2 in its absence in the first intron, an EcoRI restriction site as the rare allele in the 5'-untranslated region (5'-UTR) and an AspHI restriction site as the rare allele in the intron of the 3'-UTR. In the TNFa promoter there are four G/A exchanges in positions -376, -308 (called TNFI and TNF2), -238 and -163. TNF2 is the less frequent allele and seems to be associated with higher TNFa production. In the 5'-UTR of TNFa there is a cyto-sine-insertion polymorphism at position h-^O. resulting in an eight cytosine stretch in contrast to the normal seven cytosine stretch.

The promoter region contains the following binding sites: kB enhancer 2/CK-.I, kB enhancer i, TNI repressor site (TRS) showing a lObp sequence homologous to the AP-2 binding site, Y-box, an F.ts binding element in direct juxtaposition to an AP-1/ATF-like palindromic position, NFAT/k3 binding site of NFkB, SP-1 and a TATA-box. TNF-a induction is mostly regulated by the k3 binding site of NFkB. This k3 binding site also binds NFAT, resulting in a cyclosporine-sensitive TNFa induction. The basal 95 bp upstream of the transcription start are necessary for upregulation of TNFa expression by granulocyte-macrophage colony-stimulating factor (GM-CSF) and downregulation by interleukin 4 (IL-4). The TRS is regulated by TRS-binding proteins of 30-60 kDa.

TNFa transcription results in a primary transcript of 1.7 kbp. Regulation on the translational level predominantly occurs by controlling mRNA turnover by an UA-rich sequence in the 3'-UTR. The mRNA may be stabilized by a 38 kDa protein binding to the 3'-UTR and inhibiting translation. Furthermore, lipopolysaccharide (LPS)-stimulation downregulates this 38 kDa protein and independently enhances the initiation step of translation and formation of TNFa mRNA ribosome complexes. This or similar factors may be the reason for discrepancies observed in TNFa mRNA expression and protein release. It is not known how the elements for translational control are regulated, but endogenously increased nitric oxide (NO), cAMP or prostaglandins levels decrease TNFa production.

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