Tumor necrosis Factor (TNF) is a cytokine involved in the body's inflammatory response. TNF is in effect a peptide hormone, expressed by monocytes, fibroblasts, endothelial cells, macrophages, lymphocytes, granulocytes, smooth muscle cells, glioblastomas, and eosinophils, among other cells. The expression of the TNF gene is stimulated by the presence of interleukin-1, bacterial endotoxins, and/or platelet derived growth factor (PDGF).
TNF-alpha is a multi-functional molecule, and shows varied effects on different body tissues. Some of the important functions include stimulation of the hypothalamus to release the corticotrophin releasing hormone, stimulating the acute phase response in the liver, and stimulating phagocytosis by macrophages. An increase in the local TNF alpha concentration produces heat, swelling, redness, and pain, the classic signs of inflammation. TNF-alpha is also a potent pyrogen, and plays an active role in suppression of appetite (cachexia). The acute inflammatory response mediated by TNF is a lot of the times responsible for many of the clinical problems associated with autoimmune disorders like rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, and psoriasis. The most well- researched aspect of TNF-alpha is, however, related to its effects on cell growth and differentiation, and malignant tumor progression. It is now understood that under certain conditions, TNF stimulates cell proliferation and induces cell differentiation. At the same time, TNF has been shown to enhance the reaction of the human immune system to cancer cells, and plays a major role in the destruction of cancer cells.
The TNF-alpha gene is about 5Kb in length, and consists of five exons. The protein is 185 amino acids long, and is glycosylated at amino acid positions 73 and 172. Initially, it is synthesized in the form of a 212-amno acid long precursor form, which is then cleaved on the surface of macrophages to the shorter active version. At least five other forms of the protein are secreted by the macrophages, which differ mainly in their post-translational modifications. TNF is primarily a membrane protein. However, it exists also in an extracellular soluble form. The effect of TNF on cancer cells is probably mediated by the binding of TNF to receptors on the surface of the cancer cell, causing changes in the cell, ultimately leading to their death. Interestingly, mutations in the TNF-alpha gene have also been shown to be linked to susceptibility to cerebral malaria, as well as septic shock.
Settin et al. (2007) studied 50 children with chronic RHD (29 males and 21 females) from the Nile Delta region with rheumatic heart disease (RHD); in addition to 98 healthy unrelated controls. For all cases and controls, single nucleotide polymorphisms (SNPs) in the promoter regions of cytokine genes tumor necrosis factor (TNF)-alpha (-308) G/A, interleukin (IL)-10 (-1082 ) G/A, and IL-6 (-174) G/C as well as a variable number of tandem repeats (VNTRs) in intron 2 of the IL-1Ra gene were analyzed. All cases showed a significantly higher frequency of homozygous genotypes of TNF-alpha (-308) A/A. Cases with mitral valve disease showed a significantly higher frequency of homozygous A/A genotype of both TNF-alpha (-308) and IL-10 (-1082). The same was observed for cases with severe valve lesions. On the other hand, all studied groups showed significantly lower frequency of heterozygous genotypes of TNF-alpha (-308) G/A.
Kabir and Daar (1995) studied the role of pro- and anti-inflammatory cytokines in patients with gastric cancer. Serum samples from a total of 21 patients with advanced gastric cancer were compared to 17 healthy control individuals. Circulating TNF-Alpha levels were found to be significantly reduced by about three times in the patient group as compared to the controls.
Meenagh et al. (2002) used PCR-SSOP method to detect the frequencies of IL2 polymorphisms in different populations. Along with other populations, 80 healthy Omani blood and bone marrow donors were also used in the study. In all studied groups, the G allele of TNFA (G308A) predominated; the Omani population showed a frequency of 91.9% for this allele, while the A allele had a frequency of 8.1%. AA genotype was completely absent among the Omani population (as well as the Mexican population), while the GG genotype showed a predominance in all the studied populations (83.8% in the Omani population. Meenagh et al. (2002) showed that the TNF-alpha -308 polymorphism did not show ethnic genetic variation among the populations studied.
To investigate the susceptibility and prognostic implications of the genetic variation in TNF-a and HSP70-2 in breast carcinoma, Mestiri et al. (2001) conducted a case/control study with 243 unrelated Tunisian patients with breast carcinoma and 174 healthy control subjects and examined the associations of the clinicopathologic parameters and the genetic markers with the rates of the breast carcinoma specific overall survival (OVS) and the disease free survival (DFS). Mestiri et al. (2001) found an association between TNF2/TNF2 genotype and breast carcinoma. A high relative risk of breast carcinoma was found to be associated with one hsp70-2 homozygous genotype. The TNF2/TNF2 genotype showed a significant association with reduced DFS and OVS. Conversely, hspP2/P2 genotype is associated with increased OVS but not with DFS. Mestiri et al. (2001) indicated that genetic variation in TNF-a may represent not only markers for the increased risk of breast carcinoma but also may predict the clinical outcome.
Chouchane et al. (2001) designed a case-controlled study to investigate the potential association of stress protein (hsp70-2) and TNF-alpha gene polymorphisms with obesity. A polymerase chain reaction followed by digestion with the endonuclease NcoI was used to detect the G to A transition polymorphism at position -308 of TNF-alpha promoter region in 343 unrelated Tunisian patients with obesity and 174 healthy control subjects. Analysis of the -308 TNF-alpha polymorphism in patients with obesity and in control subjects did not reveal an association between TNF-alpha alleles and obesity. Later, Jalbout et al. (2003) designed a case-controlled study to investigate the potential association of the genetic variation of the tumor necrosis factor-alpha (TNF-alpha) with nasopharyngeal carcinoma (NPC) in Tunisians. They also investigated the association of the genetic variation of the heat shock protein 70-2 (HSP70-2) with NPC in this study. A total of 140 Tunisian patients with primary NPC and 274 healthy control subjects were investigated in this study. No association was found between genetic variations in TNF-alpha and the risk of NPC in Tunisians. Jalbout et al. (2003) suggested that the TNF2 homozygous genotype is not a susceptibility marker for NPC.
Zouari Bouassida et al. (2004) suggested that the -308 TNF-alpha polymorphism can affect the risk for diabetes type 2 as the heterozygous TNF1/TNF2 genotype might be a protective marker against diabetes type 2. The study was conducted on 280 Tunisian unrelated patients with type 2 diabetes and 274 healthy unrelated blood donors using polymerase chain reaction and restriction enzyme.