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Background: Tumor necrosis factor alpha (TNFA) is an important cytokine that influences multiple biological processes. It is one of the key mediators of acute and chronic systemic inflammatory reactions and plays a central role in several autoimmune diseases. A number of approved monoclonal antibodies (mAbs) are widely used to subside these autoimmune diseases. However, there is a high rate of non-responsiveness to treatments with these mAbs. Therefore, it is important to be able to predict responses of the patients in an individualistic manner to these therapeutic antibodies before administration. In the present study, we used in silico tools to explore the effects of missense variants in the respective epitopes of four therapeutic anti-TNFA mAbs—adalimumab (ADA), certolizumab pegol (CZP), golimumab (GLM), and infliximab (IFX)—on their interactions with TNFA. Results: The binding affinities of CZP and ADA to corresponding epitopes appear to be reduced by four (TNFAR131Q, TNFAE135G, TNFAR138Q, and TNFAR138W) and two (TNFAG66C and TNFAG66S) variants, respectively. The binding of GLM and IFX appears to be affected by TNFAR141S and TNFAR138W, respectively. TNFAG66C and TNFAG66S may be associated with autoimmune diseases, whereas TNFAE135G, TNFAR138W, and TNFAR141S may be pathogenic per se. Conclusion: These variants may contribute to the observed inter-individual variability in response to anti-TNFA mAbs treatments and be used as markers to predict responses, and thus optimize therapeutic benefits to the patients. [ABSTRACT FROM AUTHOR]

The objective of the study was to analyze the impact of TNF antagonists (TNFa) on the total cholesterol and triglycerides on ankylosing spondylitis (AS) and psoriatic arthritis (PsA). In this single-centre observational study of AS and PsA patients, differences in triglyceride and total cholesterol levels and frequency of hypertriglyceridemia and hypercholesterolemia at 3 and 6 months were analysed in patients treated and not treated with TNFa. General estimation equations and linear regression analysis were used to investigate associations between disease activity and lipid levels and to identify predictors of change. One hundred fifty-seven patients treated, and 157 not treated with TNFa , were included in the study. A transient increase in cholesterol level from baseline to 3 months in TNFa-treated patients was the only statistically significant effect ( P < 0.001). Persistent percentages of hypertriglyceridemia and hypercholesterolemia from baseline were significantly higher in not treated than in TNFa-treated patients ( P = 0.009 and P = 0.001, respectively). Inverse associations between changes in cholesterol level and Bath Ankylosing Spondylitis Disease Activity Index ( P = 0.011) and CRP ( P < 0.001), but not Disease Activity Score in 28 Joints ( P = 0.095) were found in the whole group. In AS and PsA patients treated with TNFa, mild and transient changes in cholesterol but not in triglyceride levels were associated with changes in disease activity. [ABSTRACT FROM AUTHOR]

We studied the relationship between polymorphisms rs1800629 ( -308G>A), rs28362491 ( -94ins>del), and rs3834129 ( -652ins>del) in the promoter regions of TNFA, NFKB1, and CASP8 genes, respectively, encoding TNF-α, nuclear transcription factor κB1 (NF-κB1), and caspase 8 (CASP8), and the risk and stages of chronic lymphocytic leukemia in ethnic Russians, residents of the Vyatka region of Russia. Allele -308A, genotype -308AA, and -308A genotypes ( -308AA/-308AG) were associated with the risk of this pathology (OR=1.64, 95%CI 1.14-2.37, p=0.007; OR=4.48, 95%CI 1.20-16.80, p=0.02, and OR=1.57, 95%CI 1.05-2.36, p=0.03). In addition, NFKB1 allele -94del and genotype -94del/del were associated with advanced stages of the disease at the time of diagnosis (OR=0.66, 95%CI 0.46-0.97, p=0.03 and OR=0.43, 95%CI 0.20-0.92, p=0.03). These data suggest that -308G>A and - 94ins>del polymorphisms of genes TNFA and NFKB1, respectively, can be involved in the pathogenesis of chronic lymphocytic leukemia. [ABSTRACT FROM AUTHOR]

Condensed-bicyclic 4,6-substituted1,2,4-triazolo-1,3,4-thiadiazole derivatives (CBTT) have been shown to possess a wide spectrum of pharmacological activities. In this study, several novel CBTT derivatives were synthesized and investigated for their possible role as anti-neoplastic agents. The anti-proliferative effect of various CBTT derivatives was analyzed against tumor cell lines by (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) MTT assay. One of the potential CBTT derivative, 5-(3-(2,3-dichlorophenyl)-[1,2,4]triazolo[3,4- b][1,3,4]thiadiazol-6-yl)flurobenzonitrile (DTTF) was found to be the most potent against cervical cancer SiHa cells and exhibited minimal effect against normal cells. Molecular docking analysis indicated that transcription factor NF-κB was one of the potential molecular targets modulated by DTTF. Specifically, the drug blocked the TNFα-induced phosphorylation of upstream IκBα kinase in a time-dependent manner leading to the suppression of NF-κB activation and nuclear translocation. DTTF also potentiated the apoptotic effect of TNFα, as well as significantly inhibited migration and invasion of tumor cells. Overall, these findings indicate a potential novel role and mechanism(s) of action of DTTF as an anticancer agent against diverse malignancies. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor alpha ( TNFA) is an important molecule in inflammatory, infectious, and tumoral processes. Inflammation is one of the early phases in the development of gastric cancer (GC). Therefore, several studies have examined the association of polymorphism in TNFA with gastritis and GC risk. A functional polymorphism, -308G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. To date, a number of studies have been carried out to investigate the relationship between the polymorphism and gastritis or GC susceptibility, but the results were conflicting. To investigate this inconsistency, we performed a meta-analysis of 36 studies for TNFA -308G>A polymorphism to evaluate the effect of TNFA on genetic susceptibility for gastritis and GC. An overall random-effects per-allele odds ratio of 1.16 (95 % confidence interval 1.04-1.29, P = 0.008) was found for the polymorphism. Significant results were also observed using dominant or recessive genetic models. In the subgroup analyses by ethnicity, significant results were found in Caucasians, whereas no significant associations were found among East Asians and other ethnic populations. No associations between the polymorphism and gastritis were observed. In addition, our data indicate that TNFA is involved in GC susceptibility and confers its effect primarily in diffuse type of tumors. Besides, -308G>A polymorphism was found to be significantly associated with both cardiac and noncardiac tumors. This meta-analysis demonstrated that the TNFA -308G>A polymorphism is a risk factor for developing GC, but the associations vary in different ethnic populations. [ABSTRACT FROM AUTHOR]

Background: Studies investigating the associations between tumor necrosis factor-alpha (TNFA) polymorphisms and hepatocellular carcinoma (HCC) risk report conflicting results. We conducted a meta-analysis to assess the association between TNFA gene TNFA-308(G/A), TNFA-238(G/A), TNFA-863(C/A), TNFA-857(C/T), TNFA-1031 (T/C) polymorphisms and HCC susceptibility. Methods: Two investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Database. Summary odds ratios (ORs) and 95% confidence intervals (95% CIs) for TNFA polymorphisms and HCC were calculated in a fixed-effects model (the Mantel-Haenszel method) and a random-effects model (the DerSimonian and Laird method) when appropriate. Results: This meta-analysis included 17 case-control studies, which included 2,357 HCC cases and 3,161 controls. Overall, the variant genotypes AA/AG of -308G/A were associated with a significantly increased HCC risk, when compared with GG genotype (AA vs. GG, OR = 1.97, 95%CI = 1.01-3.83; AG vs. GG, OR = 1.88, 95%CI = 1.23-2.88; AA/AG vs. GG, OR = 1.80, 95%CI = 1.19-2.72). When stratifying for ethnicity, significantly elevated HCC risk was found among Asians. Moreover, similar results were observed between TNFA-238G/A, TNFA-863C/A polymorphisms and HCC risk among Asians (for -238G/A, AG vs. GG OR = 1.63, 95%CI = 1.17-2.26, AA/AG vs. GG OR = 1.61, 95%CI = 1.16-2.24; for -863 C/A, AC vs. CC OR = 1.72, 95%CI = 1.03-2.88, AA/AC vs. CC OR = 1.71, 95%CI = 1.02-2.86), while no associations were observed between TNFA-857C/T, TNFA-1031T/C polymorphisms and HCC susceptibility. Conclusions: This meta-analysis shows that TNFA-308G/A, TNFA-238G/A and TNFA-863C/A polymorphisms may be associated with HCC among Asians. TNFA-857C/T and TNFA-1031T/C polymorphisms were not detected to be related to the risk for HCC. [ABSTRACT FROM AUTHOR]

Suggestion for a potential genetic basis to chronic rhinosinusitis (CRS) is afforded by degree of inheritability suggested from family and twin studies, existence of CRS in simple mendelian diseases, and development of sinusitis as part of the phenotype of certain gene 'knockout' murine models. Genetic association studies are expected to identify novel genes associated with CRS and suggest novel mechanisms implicated in disease development. Although these studies are subject to methodologic difficulties, associations of CRS and polymorphisms in more than 30 genes have been published, with single nucleotide polymorphisms in 3 ( IL1A, TNFA, AOAH) replicated. While the individual risk conferred by these single nucleotide polymorphisms remains modest, taken as a group, they suggest an important implication of pathways of innate immune recognition and in regulation of downstream signaling in the development of CRS. In a demonstration of these techniques' potential to identify new targets for research, the authors present a functional investigation of LAMB1, the top-rated gene from a pooling-based genome-wide association study of CRS. Upregulation of gene expression in LAMB1 and associated laminin genes in primary epithelial cells from CRS patients implicates the extracellular matrix in development of CRS and offers a new avenue for further study. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the association between cytokine gene polymorphisms and outcome following allogeneic hematopoietic SCT (allo-HSCT). A total of 138 unrelated donor/recipient pairs who underwent allo-HSCT from 2001 to 2009 were tested for TNFA-1031 (T>C), -863 (C>A), -857 (C>T), -238 (G>A), TNFB+252 (A>G) and TNFRII codon 196 (T>G) single nucleotide polymorphisms by multiplex SnaPshot analysis. Transplantation involving recipients and/or donors with TNFA-857 C/C genotype or TNFB+252 G allele-positivity resulted in a higher incidence of acute GVHD (aGVHD), which was independent of HLA mismatching. In multivariate analysis, TNFA-857 C/C genotype donors (relative risk (RR)=2.29, P=0.006) and TNFB+252 G allele-positive recipients (RR=1.789, P=0.036) were found to be significantly associated with an increased incidence of aGVHD. TNFA-857 C/C genotype donors (RR=3.748, P=0.002) and TNFB+252 G allele-positive recipients (RR=1.823, P=0.063) were also associated with the development of grades II-IV aGVHD. TNFRII polymorphism in recipients was also related to relapse rate, but no significant associations were found between TNFA, TNFB or TNFRII 196 genotype and cGVHD, relapse or overall survival after transplantation. These results provide the first report of an association between TNFA, TNFB and TNFRII polymorphic features and outcome of allo-HSCT in a Chinese population, and suggest an interaction between TNFA-857 and TNFB+252 genotypes and risk of aGVHD. [ABSTRACT FROM AUTHOR]

The effect of synthetic LVV-hemorphin-7 and hemorphin-7 on hypothalamo-pituitary-adrenocortical axis activity in response to endotoxin-induced stress was studied. The intraperitoneal (ip) endotoxin (lipopolysaccaride, LPS) (0.5 mg/kg) administration in combination with hemorphin (1 mg/kg) induce significant decrease in plasma corticosterone and modest decrease in plasma levels of tumor necrosis factor-alpha (TNFα) in compare with elevated levels of both corticosterone and TNFα in plasma of rats received LPS administration alone. Increased activity of calcineurin in both plasma and brain of rats received ip administration of LPS, was recovered under LPS + hemorphin treatment. In two independent proteome analysis, using 2-dimensional fluorescence difference gel electrophoresis and the isotope coded protein label technology, peptidyl-prolyl cis- trans-isomerase A (cyclophilin A) was identified as regulated by hemorphins protein in mouse brain. A therapeutic potential of hemorphins and mechanisms of their homeostatic action in response to endotoxin-induced stress are discussed. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-α (TNF-α) is released from mast cells via an immunoglobulin E (IgE)-dependent mechanism. The variant G>A at –308 of TNFA is part of an extended haplotype HLA-A1-B8-DR3-DQ2 and influences the gene expression. We evaluated this variant in relation to IgE-mediated reactions to betalactams, in 427 subjects, including 167 cases and 260 age- and gender-paired controls. TNFA GG genotype was a significant independent predictor of the primary risk of betalactam allergy, concurrently with total IgE level, with an age- and sex-adjusted odds ratio estimated at 2.45 (95% confidence interval: 1.18–5.08, P=0.0163). Cases with –308AA genotype had a higher serum level of specific IgE than those with –308GA/GG genotype, with median levels (relative units) of 4.6 (inter-quartiles: 3.9–10.6) and 2.2 (1.4–4.3), respectively (P=0.0046). In conclusion, our results suggest an ambivalent influence of a genetic determinant of pro-inflammatory pathways on IgE-mediated hypersensitivity to betalactams.The Pharmacogenomics Journal (2008) 8, 162–168; doi:10.1038/sj.tpj.6500456; published online 1 May 2007 [ABSTRACT FROM AUTHOR]

The practice of using discrete clinical diagnoses in genetic association studies has seldom led to a replicable genetic model. If, as the literature suggests, weak genotype–phenotype relationships are detected when clinical diagnoses are used, power might be increased by exploring more fundamental biological traits. Emerging solutions to this include directly modeling levels of the protein product of a gene (usually in plasma) and sequence variation specifically in/around that gene, as well as exploring multiple quantitative traits related to a disease of interest. Here, we attempt a strategy based upon these premises examining sequence variants near the TNF locus, a region widely studied in cardiovascular disease. Multilocus genotype models were used to perform a systematic screen of 18 metabolic and anthropometric traits for genetic association. While there was no evidence for an effect of TNF polymorphism on plasma TNF levels, a relatively strong effect on plasma PAI-1 levels did emerge (P=0.000019), but this was only evident in post-myocardial infarction patients. Modeled jointly with the common 4G/5G insertion/deletion polymorphism of SERPINE1 (formerly PAI), this effect appears large (10% of variance explained versus 2% for SERPINE1 4G/5G). We exhibit this finding cautiously, and use it to illustrate how transitioning the study of disease risk to quantitative traits might empower the identification of functionally variable genes. Further, a case is highlighted where association between sequence variation in a gene and its product is not readily apparent even in large samples, but where association with a down-stream pathway may be.European Journal of Human Genetics (2007) 15, 685–693. doi:10.1038/sj.ejhg.5201803; published online 14 March 2007 [ABSTRACT FROM AUTHOR]

To assess the role that polymorphisms of cytokine genes play in genetic predisposition to chronic obstructive pulmonary disease (COPD), the allele and genotype distributions of IL1B, IL1RN, TNFA, LTA, IL6, IL8, and IL10 were studied in COPD patients ( N = 319) and healthy individuals ( N = 403), residents of Ufa, Bashkortostan. Genotype IL1RN*2/IL1RN*2 of IL1RN was identified as a risk factor for COPD, its frequency being 9.80% in the COPD patients and 4.67% in the healthy subjects ( x 2 = 5.45, df = 1, P = 0.02, OR = 2.21). Genotype GG of the LTA polymorphism A252G was significantly more common in the COPD patients than in the controls (7.84% vs. 3.72%; x 2 = 5.00, df = 1, P = 0.026). In patients with COPD stage IV, the frequency of this genotype was twice as high as in those with COPD stages II and III (11.18% vs. 4.79%; x 2 = 3.08, df = 1, P = 0.08). Genotype GG of the TNFA polymorphism G(−308)A in combination with genotype AA of the LTA polymorphism A252G was significantly less frequent in the COPD patients than in the healthy subjects (38.55% vs. 46.93%; x 2 = 8.82, df = 1, P = 0.0039). Genotype GG of the IL6 polymorphism G(−174)C was more frequent in the patients with COPD stage IV (43.75% vs. 31.54% in the patients with COPD stages II and III, x 2 = 4.15, P = 0.042). No significant differences were found between the groups of COPD patients and healthy subjects concerning the genotype frequencies of the polymorphisms T(−511)C and T3953C of IL1B, G(−308)A of TNFA, G(−174)C of IL6, A(−251)C of IL8, and C(−627)A of IL10. [ABSTRACT FROM AUTHOR]

Dramatic clinical success in the treatment of chronic inflammatory diseases has resulted from the use of anti-cytokine therapies including specific blocking antibodies, soluble receptors and traps to silence the actions of inflammatory cytokines such as tumour necrosis factor alpha (TNFa) and interleukin-1 (IL-1). Two agents used clinically to block the functional activity of TNFa protein are Remicade (an antibody) and Enbrel (a soluble TNF receptor). These tools are now being extended to many other clinical disorders. We have a specific interest in the treatment of muscle diseases. In order to study the effects of novel anti-cytokine drugs on mouse models of human disease, such drugs must be investigated to determine whether they are indeed effective in blocking the inflammatory response in mouse. This has been carried out by means of a simple in vivo bioassay. Histological examination of transverse sections from whole muscle autografts in C57BL/10ScSn mice sampled at 5 days after transplantation provides an excellent assay model and clearly shows that Remicade and Enbrel block the acute inflammatory cell response in vivo. This graft model has also been used to show that a single intraperitoneal injection of Remicade (10 µg/g) is long-lived and effective when administered at 1 week and even 4 weeks prior to the assay. Enbrel is highly effective when injected twice at -3 days and -1 day (2×100 µg) before muscle grafting but shows no inhibition of the inflammatory response after a single injection (100 µg) 1 week prior to grafting. This striking ablation of inflammation by pharmacological blockage of TNFa is in marked contrast to the lack of any effect in TNFa null mice. This simple reproducible in vivo assay model in mice can be used to evaluate the efficacy of many novel anti-cytokine interventions designed to block inflammation. [ABSTRACT FROM AUTHOR]

Mechanisms underlying susceptibility to skin irritants are not clearly understood. Cytokines play a key role in inflammation, and functional polymorphisms in cytokine genes may affect responses to irritants. We investigated the relationship between polymorphism in the tumor necrosis factor (TNF) α-chain gene and responses to irritants. Volunteers (n=221) tested with sodium dodecyl sulfate (SDS) and benzalkonium chloride (BKC) were divided into responders and nonresponders and high and low irritant-threshold groups. DNA was assayed for the TNF-308 polymorphism by a polymerase chain reaction-restriction fragment length polymorphism method. There was a significant increase in the A allele (P=0.030) and AA genotype (P=0.023) in both the SDS low irritant-threshold group and in SDS responders (A allele P=0.022, AA genotype P=0.048). In the BKC low irritant-threshold group, we found a significant increase in the A allele (P=0.002) and AA genotype (P=0.016). Individuals with a low threshold to both irritants demonstrated a significant increase (P=0.002) in the A allele. This is the first description of a nonatopic genetic marker for irritant susceptibility in normal individuals. Genotyping for theTNF-308 polymorphism may thus contribute to screening of individuals deemed at risk of developing irritant contact dermatitis. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor alpha ( TNFA) is a cytokine, which is secreted from activated macrophage, with a broad range of biological activities. The gene encoding TNFA is located in tandem with the TNFB gene within the HLA complex on chromosome 6p21.3. We detected a single base polymorphism in the human TNFA gene promoter region in 300 unrelated Korean individuals. The TNFA promoter region which showed a G to A transition at position of −308 was investigated by NcoI restriction fragment length polymorphism analysis. A biallelic polymorphism of TNFA gene showed fragments of 87/20 bp and 107 bp acting as TNFA*1 allele and TNFA*2 allele, respectively. The allele frequencies of TNFA*1 and TNFA*2 were 0.8783 and 0.1217, respectively. The 21.7% of heterozygosity was observed. No association between promoter region phenotypes of TNFA and the first intron phenotypes of TNFB was observed in Korean. Allele frequencies of Koreans were compared with that of Europeans. [ABSTRACT FROM AUTHOR]

TNFα inhibitors are more widely used in the treatment of intraocular inflammation, thus ophthalmologists should become aware of possible adverse events, associated with this form of treatment. Herein we report two cases of cutaneous adverse events in uveitis patients treated with infliximab. In one patient, the primary outbreak of pustular psoriasis was observed after her third infusion. A second patient developed impetigo contagiosa induced by Staphylococcus aureus. Thus patients undergoing treatment with infliximab should be monitored carefully since dermal infections and pustular psoriasis, which may be triggered by streptococcal infection, may occur under this regime.Eye (2007) 21, 547–549. doi:10.1038/sj.eye.6702262; published online 3 February 2006 [ABSTRACT FROM AUTHOR]

Allele frequencies of TNFa and TNFb microsatellites were determined from 315 healthy unrelated Germans (mothers and putative fathers) by means of PCR. They were stably inherited and segregated in a Mendelian way. New mutations were not observed. [ABSTRACT FROM AUTHOR]