Figure 1 (B) The region from -618 to +192 of the TNF gene is shown in full sequence including the polymorphisms (G/A exchanges and C-stretch). The binding sites for transcription factors (bold letters) are underlined for each factor, overlapping binding sites for two factors are underlined twice. The promoter region contains the following binding sites: kB enhancer 2/CK-1, kB enhancer 3, TNF repressor site (TRS) showing a 10bp sequence homologous to the AP-2 binding site, Y-Box, an Ets 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 cyclosporin A sensitive TNF-a induction.
IL-1 and GM-CSF in synovial cells. However, there is a strong synergism between TNFa and IL-1 in the induction of human articular cartilage degradation during prolonged culture.
In collagen-induced arthritis in mice and rats, the involvement of TNFa has been shown, in that application of rTNFa leads to an accelerated onset and a more severe course of the disease. Infusion of sTNFR or anti-TNFa reduces the frequency and severity of collagen-induced arthritis. TNFa serum levels in RA correlate positively with the number of activated T cells (CD37HLA-DR+ and CD37CD25") and in acute rheumatic fever, the number of CD47CD25' cells is enhanced. Mycoplasma arthritidis-derived superantigen (MAS), as a pathogenic factor of this arthritogenic organism, induced TNFa in human T cells and not in monocytes, corresponding to the detected activated T cells in RA.
Furthermore, IL-10 counteracts TNFa in RA, whereas TNFa counteracts TGFß to induce a2(I) collagen gene transcription. This may contribute to the hypothesis that cartilage damage is a combination of destruction and ineffective rebuilding. It was shown that TNFa concentrations correlated with the extent of a,-antitrypsin in synovial fluid of RA patients.
In preclinical studies, anti-TNFa treatment of RA patients has a beneficial effect. This important role of TNFa in RA in combination with the defined HLA associations triggered the hypothesis of an association with some TNFa alleles. However, there are no associations between TNFß polymorphism and RA.
Insulin-dependent diabetes mellitus (IDDM)
TNFa is directly involved in the destruction of pancreatic ß cells. Furthermore, in the IDDM animal models it is established that islet-infiltrating mononuclear cells produce TNFa. IDDM is associated with the haplotypes TNFB'"2, TNFa2 and TNFa 1 b5. However, the associated TNF haplotypes are in linkage disequilibrium with HLA haplotypes which are established as being associated with IDDM.
Autoimmune diseases Rheumatoid arthritis (RA)
Elevated levels of TNFa are present in about 50% of samples of rheumatoid synovial fluid, particularly in those patients with more severe disease or with high white blood cell counts in synovial fluid. However, high levels of TNFa do not correspond to biological activity, because sTNFR is also enhanced in the fluids. In vitro it has been observed that antibodies to TNFa inhibit the spontaneous release of
Was this article helpful?
Did You Know That Herbs and Spices Have Been Used to Treat Rheumatoid Arthritis Successfully for Thousands of Years Do you suffer with rheumatoid arthritis Would you like to know which herbs and spices naturally reduce inflammation and pain 'Treating Rheumatoid Arthritis with Herbs, Spices and Roots' is a short report which shows you where to start.