tnf - tumor necrosis factor
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Pubmed
Journal: Infection and immunity
September/3/2002
Abstract

Mannheimia (Pasteurella) haemolytica A1 produces several virulence factors that play an important role in the pathogenesis of bovine pneumonic pasteurellosis. Foremost among these is a leukotoxin (LKT) that specifically kills ruminant leukocytes. Recent evidence suggests that M. haemolytica LKT binding to bovine leukocytes is mediated by the beta(2)-integrin CD11a/CD18 (lymphocyte function-associated antigen 1 [LFA-1]), which subsequently induces activation and cytolysis of these cells. Inflammatory cytokines, which are released during viral and bacterial infection, are reported to increase LFA-1 expression and conformational activation. We investigated the effects of the inflammatory cytokines interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and gamma interferon (IFN-gamma) on the interaction of M. haemolytica LKT with bovine peripheral blood neutrophils (PMNs). In this study we demonstrated, by flow cytometry, that bovine PMNs increased their binding to an anti-bovine LFA-1 monoclonal antibody (BAT75A) following in vitro incubation with IL-1beta, TNF-alpha, or IFN-gamma. Incubation with cytokines also increased CD18 expression, as assessed by real-time PCR and by Western blotting. Increased LFA-1 expression by PMNs exposed to cytokines was associated with increased LKT binding and cytotoxicity. The latter represented, at least in part, enhanced PMN apoptosis, as assessed by propidium iodine staining and caspase-3 activation. The results of this study suggest that inflammatory cytokines may play an important role in enhancing the biological response of bovine PMNs to M. haemolytica LKT.

Pubmed
Journal: Carcinogenesis
April/11/2001
Abstract

It has been proposed that the cytokine tumor necrosis factor alpha (TNFalpha) stimulates peroxisome proliferator-induced hepatic cell proliferation. To test this hypothesis, induction of peroxisome proliferation and hepatocyte proliferation were compared in wild-type C57Bl/6 and TNFalpha knockout mice. Animals were dosed with either vehicle or 100 mg/kg/day WY14,643 by oral gavage for 4 days. Liver to brain weight ratios increased in both wild-type and TNFalpha knockout animals after WY14,643 administration. In addition, WY14,643-treated wild-type C57Bl/6 and TNFalpha knockout mice displayed marked hepatic induction of fatty acyl-CoA oxidase activity (approximately 8-fold) and mRNA content (approximately 5-fold). Electron microscopic examination confirmed increased numbers of peroxisomes in hepatocytes in both mouse models. Moreover, WY14,643 markedly induced hepatic cell proliferation (approximately 15-fold) in both wild-type C57Bl/6 and TNFalpha knockout mice as measured by bromodeoxyuridine incorporation into hepatocyte nuclei. In addition, a 50% decrease in TNFalpha mRNA was observed in wild-type mice after treatment with WY14,643. These results suggest that the hepatocellular proliferation induced after peroxisome proliferator treatment occurs independently of TNFalpha signaling.

Pubmed
Journal: The Journal of biological chemistry
October/13/2014
Abstract

Microbes are detected by the pathogen-associated molecular patterns through specific host pattern recognition receptors. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an intracellular pattern recognition receptor that recognizes fragments of the bacterial cell wall. NOD2 is important to human biology; when it is mutated it loses the ability to respond properly to bacterial cell wall fragments. To determine the mechanisms of misactivation in the NOD2 Crohn mutants, we developed a cell-based system to screen for protein-protein interactors of NOD2. We identified heat shock protein 70 (HSP70) as a protein interactor of both wild type and Crohn mutant NOD2. HSP70 has previously been linked to inflammation, especially in the regulation of anti-inflammatory molecules. Induced HSP70 expression in cells increased the response of NOD2 to bacterial cell wall fragments. In addition, an HSP70 inhibitor, KNK437, was capable of decreasing NOD2-mediated NF-κB activation in response to bacterial cell wall stimulation. We found HSP70 to regulate the half-life of NOD2, as increasing the HSP70 level in cells increased the half-life of NOD2, and down-regulating HSP70 decreased the half-life of NOD2. The expression levels of the Crohn-associated NOD2 variants were less compared with wild type. The overexpression of HSP70 significantly increased NOD2 levels as well as the signaling capacity of the mutants. Thus, our study shows that restoring the stability of the NOD2 Crohn mutants is sufficient for rescuing the ability of these mutations to signal the presence of a bacterial cell wall ligand.

Pubmed
Journal: The Journal of infectious diseases
November/21/2002
Abstract

The intensity of malaria transmission is related to the pattern of malarial disease observed in different regions, but populations may also differ in their underlying predispositions to severe malarial anemia or cerebral malaria. In western Kenya, where severe malarial anemia is much more common than cerebral malaria, the distributions of tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, transforming growth factor (TGF)-beta, IL-6, and interferon (IFN)-gamma alleles were examined in a cohort of young men. The cohort displayed a marked bias toward genotypes associated with low expression of IFN-gamma and IL-6, cytokines that, at high levels, have been implicated in malarial anemia and poor malaria outcomes. By contrast, the frequency of the TNF-alpha -238A allele, which has been associated with severe malarial anemia, was found to be similar to the frequency previously reported in comparison populations in Africa and elsewhere. IFN-gamma and IL-6 genotypes may play roles in the development of severe malaria and could contribute to the relative frequency of severe malarial anemia or cerebral malaria in exposed populations.

Pubmed
Journal: Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis
June/28/2006
Abstract

BACKGROUND

The correction of anemia by recombinant human erythropoietin (rHuEPO) improves quality of life and prolongs life in end-stage renal failure. rHuEPO requirements for an individual are determined by a range of factors, including iron deficiency and inflammation. Single nucleotide polymorphisms in the promoter sequence of several proinflammatory cytokines have been shown, in different fields of medicine, to influence the cytokine response to different stimuli, with effects on clinical outcome.

METHODS

The angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and polymorphisms in the promoter regions of the genes for tumor necrosis factor alpha (-308 A/G), interleukin-6 (-174 G/C), and interferon gamma were examined for their association with rHuEPO requirements in 112 patients on continuous ambulatory peritoneal dialysis (CAPD). Genomic DNA was extracted from peripheral blood leukocytes and genotyping performed with ARMS-PCR methodology, with sequence-specific primers. We examined rHuEPO requirements and C-reactive protein at baseline and during a 6-month study period.

RESULTS

We found no significant effect of proinflammatory cytokine polymorphisms on rHuEPO responsiveness. However, throughout the study, we observed that there was a significantly higher rHuEPO requirement in the II and ID ACE genotypes compared with the DD group, which remained an independent association following multivariate analysis.

CONCLUSIONS

ACE insertion/deletion polymorphism may determine rHuEPO responsiveness in CAPD patients and should be considered in relative rHuEPO resistance.

Pubmed
Journal: Journal of immunology (Baltimore, Md. : 1950)
July/11/2007
Abstract

TNF and its receptors p55 and p75 are known to be important in the homeostasis of the peripheral immune system. Previous studies have presented apparently contradictory evidence for an in vivo role of TNF in T cells. In this study, we analyzed TNF-deficient mice crossed with the F5 TCR-transgenic animals. We show that endogenous TNF modulates several aspects of homeostasis of peripheral F5 CD8 T cells. We found that F5/TNF(-/-)mice had reduced numbers of peripheral F5 T cells, F5/TNF(-/-) CD8 T cells exhibited reduced survival potential, and furthermore that T cell-derived TNF is required for optimum recovery of naive CD8 T cells in lymphopenic hosts, suggesting its involvement in the survival of peripheral CD8 T cells. Both peptide activation and ensuing Ag-induced apoptosis are quantitatively reduced in TNF(-/-) CD8 T cells. The latter observations can be related to decreased binding activities of NF-kappaB and NF-ATp observed in Ag-stimulated F5/TNF(-/-) T cells. Finally, in a CD8 T cell tolerance model, endogenous TNF was necessary for several parameters of CD8 T cell tolerance induction. Collectively, our results provide evidence that endogenous TNF modulates thresholds in several ligand-driven T cell responses.

Pubmed
Journal: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
May/23/2007
Abstract

The roles of free fatty acids (FFA), tumor necrosis factor-alpha (TNF-alpha), and adiponectin in the development of the insulin-resistant metabolic disorder in several subjects have been studied. A total of 70 Japanese male subjects were selected according to the following three sets of criteria: subjects in group A had, (1) a fasting plasma glucose (FPG)>or=110 to <140 mg/dl, (2) a triglyceride (TG) level>or=150 mg/dl, (3) a systolic blood pressure (SBP)>or=140 and/or diastolic blood pressure (DBP)>or=90 mmHg, and (4) a body mass index (BMI)>or=25 kg/m2 (age=53.4+/-8.5 years, BMI=27.0+/-1.3 kg/m2, n=16). Subjects in group B had, (1) FPG<110 mg/dl, (2) TG<150 mg/dl, (3) SBP<140 and DBP<90 mmHg, and (4) BMI>or=25 kg/m2 (age=47.2+/-10.3 years, BMI=26.6+/-1.31 kg/m2, n=38). Subjects in group C had, (1) FPG<110 mg/dl, (2) TG<150 mg/dl, (3) SBP<140 and DBP<90 mmHg, and (4) 20>or=BMI<22 kg/m2 (age=50.4+/-9.3 years, BMI=20.9+/-0.6 kg/m2, n=16). The homeostasis model assessment of insulin resistance in group A (2.7+/-1.4) was significantly higher (p<0.0001) than in groups B (1.6+/-0.7) and C (0.9+/-0.5). FFA in group A (1.17+/-0.57 mEq/l) was significantly higher than in groups B (0.62+/-0.23 mEq/l) and C (0.48+/-0.16 mEq/l) (p<0.0001). Serum TNF-alpha in group A (1.36+/-0.62 pg/ml) was significantly higher than in groups B (0.95+/-0.35 pg/ml; p=0.003) and C (0.76+/-0.09 pg/ml; p=0.0013). No significant differences in the serum level of adiponectin were observed between groups A and B or between groups B and C. The results suggest that FFA and possibly TNF-alpha levels are closely related to the development of insulin resistance in subjects with metabolic disorders.

Pubmed
Journal: American journal of physiology. Gastrointestinal and liver physiology
September/8/2013
Abstract

Cell line studies have previously demonstrated that hypoxia-reoxygenation (H/R) leads to the production of NADPH oxidase 1 and 2 (NOX1 and NOX2)-dependent reactive oxygen species (ROS) required for the activation of c-Src and NF-κB. We now extend these studies into mouse models to evaluate the contribution of hepatocytes to the NOX- and c-Src-dependent TNF-α production that follows H/R in primary hepatocytes and liver ischemia-reperfusion (I/R). In vitro, c-Src-deficient primary hepatocytes produced less ROS and TNF-α following H/R compared with controls. In vivo, c-Src-KO mice also had impaired TNF-α and NF-κB responses following partial lobar liver I/R. Studies in NOX1 and p47phox knockout primary hepatocytes demonstrated that both NOX1 and p47phox are partially required for H/R-mediated TNF-α production. To further investigate the involvement of NADPH oxidases in the production of TNF-α following liver I/R, we performed additional in vivo experiments in knockout mice deficient for NOX1, NOX2, p47phox, Rac1, and/or Rac2. Cumulatively, these results demonstrate that NOX2 and its activator subunits (p47phox and Rac) control the secretion of TNF-α by the liver following I/R. Interestingly, in the absence of Kupffer cells and NOX2, NOX1 played a dominant role in TNF-α production following hepatic I/R. However, NOX1 deletion alone had little effect on I/R-induced TNF-α. Thus Kupffer cell-derived factors and NOX2 act to suppress hepatic NOX1-dependent TNF-α production. We conclude that c-Src and NADPH oxidase components are necessary for redox-mediated production of TNF-α following liver I/R and that hepatocytes play an important role in this process.

Pubmed
Journal: International journal of clinical oncology
January/10/2017
Abstract

BACKGROUND

Cytokine-mediated inflammation is important in the pathogenesis of non-small cell lung cancer (NSCLC). Genetic polymorphisms in cytokine genes and their association with lung cancer in the Indian population have not been reported.

METHODS

For the first time, we analyzed genetic polymorphisms of TNFα -308, IFNγ +874, and IL10 -1082 genes in 246 NSCLC patients and 250 healthy controls in the South Indian population from Telangana using ARMS PCR.

RESULTS

IFNγ+874 A/T and IL10-1082 G/G gene polymorphisms were found to be significantly associated with NSCLC with 1.56- and 1.68-fold disease risk, respectively. There was no association between the risk of NSCLC and TNFα-308 polymorphism. Gene polymorphisms stratified according to smoking revealed that IFNγ+874 A/T polymorphisms in smokers increased the disease risk by 2.91 fold. IL10-1082 G/G polymorphisms showed 2-fold increased risk among patients who were smokers when compared to the controls. However, there was no association between TNFα-308, IFNγ+874, and IL10-1082 gene polymorphism and the stage of the NSCLC patients. The overall risk associated with the combination of these polymorphisms indicated that the TNFα-308 G/A + IFNγ+874 A/T + IL10-1082 G/G genotype increased the risk by 1.5 fold.

CONCLUSIONS

The results of our study indicate an association between cytokine gene polymorphisms and the risk of NSCLC in an Indian population.

Pubmed
Journal: Investigative ophthalmology & visual science
February/13/2013
Abstract

OBJECTIVE

This study evaluates the effects of the gold nanoparticle in endotoxin-induced uveitis in rats.

METHODS

Adult male Wistar rats were divided into five groups: saline + saline, lipopolysaccharide (LPS) + saline, LPS + prednisolone, LPS + gold salt (GS) and LPS + gold nanoparticle (GNP). Two hours after LPS administration, prednisolone acetate 1%, GS, and GNP were topically applied to both eyes of rats and repeated every 6 hours for 24 hours. After 24 hours, rats were anesthetized and aqueous humor was sampled and the irides were removed. Aqueous humor TNF-α, myeloperoxidase activity were determined. Irides oxidative damage and content of toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) were determined.

RESULTS

The administration of LPS-induced eye inflammatory response characterized by an increase in aqueous humor TNF-α, myeloperoxidase, and by irides oxidative damage. All these parameters were decreased by the administration of GNP. Since the inflammatory response secondary to LPS administration depends, in part, to the activation of the TLR4-NF-κB pathway we demonstrated here that a potential mechanism to explain the GNP effects was the decrease on TLR4 content and NF-κB activation.

CONCLUSIONS

These findings suggest that topical GNP decreases intraocular inflammation and oxidative damage by interfering in the TLR4-NF-κB pathway.

Pubmed
Journal: Journal of occupational and environmental medicine
October/11/2006
Abstract

OBJECTIVE

The objective of this study was to estimate the contribution of lifestyle (cigarettes) and tumor necrosis factor (TNF) alpha polymorphisms at position 308 of the tumor necrosis factor alpha gene promotor (TNF-308*1/*2) to pulmonary function among grain handlers.

METHODS

Employed male grain handlers (157) provided occupational and respiratory symptom information, pulmonary function measurements, and DNA for genotyping.

RESULTS

The genotypes of 101 were TNF-308*1/*1, 47 were *1/*2, and nine were *2/*2. Current smokers whose genotype was *2/*2 or *1/*2 had lower values compared with other combinations of genotype and smoking status. Among *1/*1 homozygotes, current smokers had better percent of predicted forced expiratory volume in 1 second (P = 0.04) mean values than nonsmokers and better percent of predicted forced vital capacity than exsmokers (P = 0.017) or nonsmokers (P = 0.008).

CONCLUSIONS

These results indicate the complexity of determining which workers will develop acute and chronic adverse pulmonary conditions in response to exposure to grain dust and the toxins in cigarette smoke interacting with their genotype.

Pubmed
Journal: The Journal of infectious diseases
November/26/2007
Abstract

Bordetella pertussis causes whooping cough, an endemic respiratory disease that is increasing in prevalence despite vaccination efforts. Although host immunity is modulated by virulence factors of this pathogen, it is unclear what host factors are required to overcome their effects. Here, we investigate an apparent relationship between the effects of pertussis toxin and tumor necrosis factor (TNF)- alpha . B. pertussis grew efficiently and caused moderate pathology in wild-type mice, whereas TNF- alpha (-/-) mice had higher numbers of bacteria and leukocytes in lungs, experienced more airway resistance, and died of the infection. Interestingly, an isogenic B. pertussis strain lacking pertussis toxin did not induce these effects in TNF- alpha (-/-) mice and behaved similarly in wild-type and TNF- alpha -deficient hosts. Together, these results indicate that TNF- alpha is essential for the host to overcome the effects of pertussis toxin, allowing both control of B. pertussis numbers and regulation of the inflammation induced by infection.

Pubmed
Journal: European journal of obstetrics, gynecology, and reproductive biology
December/29/2005
Abstract

OBJECTIVE

Osteoporosis is a common disorder with a strong genetic component. We investigated the correlations between bone mineral density (BMD) and four gene polymorphisms (-308G>A tumor necrosis factor alpha (TNF-alpha), -34T>C CYP 17, *141T>C urokinase, and -627C>A interleukin 10 (IL-10) promoter), and their relationship to osteoporosis in postmenopausal women.

METHODS

These polymorphisms were determined using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. BMD of the lumbar spine and proximal femur were measured using dual-energy X-ray absorptiometry.

RESULTS

The prevalence of each genotype was as follows: (1) 79.3% A/A, 16.6% A/G, and 4.1% G/G in -308G>A TNF-alpha; (2) 18.9% T/T, 52.1% T/C, and 29% C/C in -34T>C CYP 17; (3) 86.4% C/C and 13.6% C/T in *141T>C urokinase; (4) 46.2% A/A, 45% A/C, and 8.8% C/C in -627C>A IL-10 promoter. Subjects with genotype C/C in -627C>A IL-10 promoter had lower BMD values and a significantly greater risk for osteoporosis (OR 8.1, 95% CI 1.5-42.8) at the lumbar spine compared with subjects with genotype A/C in -627C>A IL-10 promoter, after adjustment for potential confounders.

CONCLUSIONS

The RsaI IL-10 promoter gene polymorphism is associated with reduced BMD and predisposes women to osteoporosis at the lumbar spine.

Pubmed
Journal: The Journal of urology
May/2/2001
Abstract

OBJECTIVE

We tested the hypothesis that genotype changes in the promoter region of tumor necrosis factor-alpha and exon 1 are associated with renal cell carcinoma.

METHODS

We analyzed genotypic changes at the 3 polymorphic loci of tumor necrosis factor-alpha -238, -308 and 488 using tumor and normal tissues from 81 Japanese patients with renal cell carcinoma.

RESULTS

Of the 81 patients 14 (17%) had point mutations from G to A, including 8 (57%) with point mutations at multiple loci. Six of the 8 patients (75%) with point mutations at multiple loci were classified with stage 4 renal cell carcinoma. Of the 81 patients 14 were classified with stage 4 carcinoma, including 9 (64%) with point mutation from G to A. Normal tissue from cancer patients showed an increased frequency of the GA genotype at loci -238 and 488 compared to healthy controls (37% versus 9% and 30% versus 12%, respectively). The relative risk of renal cell carcinoma was 6.5-fold higher in patients with the GA genotype at locus -238 (p <0.001) and 2.9-fold higher in those with the GA genotype at locus 488 (0.01 < p <0.025) when comparing normal tissue from renal cell carcinoma patients with that of healthy controls.

CONCLUSIONS

Point mutation from G to A, and the GA genotype at loci -238 and 488 of the TNF-alpha gene were common in patients with advanced renal cell carcinoma. The genotype change at loci -238 and 488 of the TNF-alpha gene are associated with renal cancer pathogenesis.

Pubmed
Journal: European journal of obstetrics, gynecology, and reproductive biology
July/7/2010
Abstract

OBJECTIVE

The imbalance between pro- and anti-inflammatory cytokines and polymorphism of cytokine genes may play a role in the etiology of the polycystic ovary syndrome (PCOS). The aim of this study was to investigate the association of polymorphisms of TNFalpha, IL-6 and IL-10 genes with the occurrence and the clinical/laboratory characteristics of PCOS in the Turkish population.

METHODS

Single nucleotide polymorphisms (SNPs) of TNFalpha (-308 G/A), IL-6 (-174 G/C), IL-10 (-1082 G/A) genes in DNA from peripheral blood leukocytes of 97 PCOS patients and 95 healthy control women were investigated.

RESULTS

There is a tendency toward lower frequency of the IL-6 CC genotype and C allele among PCOS women compared with healthy controls although the difference did not reach a significant level. No notable differences were observed in allele or genotype frequencies for TNFalpha and IL-10 genes between groups. The concomitant presence of wild homozygous TNFalpha genotype together with mutant IL-6 C allele has a protective effect against PCOS with an OR=0.45 (95% CI=0.23-0.86). While TNFalpha (-308) and IL-10 (-1082) genotypes did not influence clinical/laboratory parameters in PCOS, IL-6 (-174) CC or pooled CG+CC genotypes have lower glucose, insulin, HOMA, cholesterol, triglyceride, and LDL-C, and higher GIR and HDL-C values than GG genotypes.

CONCLUSIONS

We suggest that the IL-6 promoter region polymorphism may be related to occurrence and metabolic abnormalities seen in PCOS in the Turkish population. However, more studies with larger sample size are necessary to support our findings in other populations before any statement can be made about the relationship between PCOS and cytokine polymorphism.

Pubmed
Journal: Gut
March/22/2004
Abstract

OBJECTIVE

The solute carrier family 11 member 1 (SLC11A1) gene (formerly Nramp1) encodes for the protein solute carrier family 11, member 1. It affects susceptibility and clinical outcome of autoimmune and infectious diseases. We investigated the possible role of the functional polymorphism located in the promoter region of SLC11A1 and tumour necrosis factor (TNF) genes in the progression of fibrosis in chronic hepatitis C.

METHODS

A total of 242 Caucasian Spanish patients with biopsy proven chronic hepatitis C and 194 healthy control subjects were genotyped for SLC11A1 and TNF promoter polymorphisms.

RESULTS

No significant differences in the distribution of frequencies among patient and control groups were observed. The SCL11A1 homozygous 2/2 genotype was rarely detected among patients showing advanced fibrosis (2/82; 2.4%) but was highly represented in those with mild fibrosis (29/160; 18.1%; odds ratio (OR) 8.85 (95% confidence interval (CI) 1.9-55.2, p(c) = 0.002). In patients carrying allele 3 of SLC11A1, the presence of -238 TNF A/G was associated with advanced fibrosis (14/26 (53.8%) v 68/216 (31.4%); OR 2.53 (95% CI 1.03-6.23); p = 0.02).

CONCLUSIONS

SLC11A1 gene promoter polymorphism could influence fibrosis progression in chronic hepatitis C in that the homozygous genotype 2/2 exerts a protective effect against cirrhosis development. Also, the combination of TNF -238 A/G and the presence of allele 3 is conducive to progression to pre-cirrhotic or cirrhotic stages of the disease.

Pubmed
Journal: Cancer biomarkers : section A of Disease markers
February/7/2016
Abstract

BACKGROUND

The pro-inflammatory cytokines play an essential role in immune response and are involved in a variety of inflammatory and infectious disease. Tumor necrosis factor alpha (TNF-α) gene polymorphism has been a potential determinant of susceptibility to various types of cancer.

OBJECTIVE

To evaluate the association of TNF-α gene promoter (-238) G/A and (-308) G/A polymorphisms with the susceptibility of OSCC patients in North Indian population.

METHODS

A total 272 patients with OSCC and 185 healthy volunteers were genotypes for the TNF-α (-238) G/A and (-308) G/A gene polymorphism. Genotypes were identified by polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). Genotype frequencies were evaluated by Chi-square test and Odds ratio (OR) relative risk.

RESULTS

TNF-α (-238) G/A polymorphism was significantly associated with OSCC patients as compared to healthy volunteers (GG vs. GA: OR=0.3500, 95% CI=0.1289-09502; p=0.036; G vs. A: OR=0.3589 1.477, 95% CI=0.1335-0.9652; p=0.0386). No significant association was found in TNF-α (-308) G/A gene polymorphism with OSCC patients and controls.

CONCLUSIONS

We conclude that the TNF-α (-238) G/A polymorphism was significantly associated with OSCC however TNF-α (-308) G/A polymorphism was not associated in OSCC patients.

Pubmed
Journal: Cytokine
May/11/2010
Abstract

OBJECTIVE

Previous studies have established that hydrolysis of LDL by Group V secretory phospholipase A(2) (GV sPLA(2)) generates a modified particle capable of inducing macrophage foam cell formation. The aim of the present study was to determine whether GV sPLA(2)-hydrolyzed LDL (GV-LDL) produces pro-atherogenic effects in macrophages independent of cholesterol accumulation.

RESULTS

J-774 cells incubated with GV-LDL produced more TNF-alpha and IL-6 compared to cells incubated with control-LDL. Indirect immunofluorescence showed that GV-LDL but not control-LDL induced nuclear translocation of NFkappaB. Inhibitors of NFkappaB activation, effectively blocked cytokine production induced by GV-LDL. Control-LDL and GV-LDL were separated from albumin present in reaction mixtures by ultracentrifugation. The albumin fraction derived from GV-LDL contained 80% of the FFA generated and was more potent than the re-isolated GV-LDL in inducing pro-inflammatory cytokine secretion. Linoleic acid (18:2) and oleic acid (18:1) were the most abundant FFAs generated, whereas newly formed lyso-PCs contained 14:0 (myristic), 16:1 (palmitic), and 18:2 fatty acyl groups. Experiments with synthetic FFA showed that 18:1 induced J-774 cells to secrete TNF-alpha and IL-6.

CONCLUSIONS

These results indicate that in addition to promoting atherosclerotic lipid accumulation in macrophages, GV sPLA(2) hydrolysis of LDL leads to activation of NFkappaB, a key regulator of inflammation.

Pubmed
Journal: The Journal of general virology
February/29/2004
Abstract

Hepatitis C virus (HCV) has been reported to replicate in monocytes/macrophages in infected patients. However, it is unclear whether macrophages are susceptible to infection in vitro and whether such an infection is consequential. Sera from 26 HCV-infected patients were incubated with primary human macrophages collected from healthy donors. Virus negative strand was detected by a Tth enzyme-based strand-specific assay and virus sequences were analysed by single strand conformation polymorphism (SSCP) and sequencing. Concentrations of the cytokines tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta, IL-6, IL-8, IL-10 and IL-12p70 were measured in culture supernatants and respective mRNAs were analysed in cell extracts by quantitative RT-PCR. For 15 sera, HCV RNA was detectable in 2- and 3-week cultures from at least one donor. Virus negative strand was detected in 29 % of macrophage samples in this group. In four cases, HCV RNA sequences amplified from macrophages differed from those amplified from sera suggesting evolution during infection. Concentrations of TNF-alpha and IL-8 were found to be significantly higher in supernatants from HCV-infected cultures. In conclusion, these preliminary data suggest that primary human macrophages are susceptible to HCV infection in vitro and this infection is associated with the induction of cytokines TNF-alpha and IL-8.

Pubmed
Journal: Journal of neurophysiology
February/17/2016
Abstract

Tetrodotoxin-resistant (TTX-r) sodium channels are key players in determining the input-output properties of peripheral nociceptive neurons. Changes in gating kinetics or in expression levels of these channels by proinflammatory mediators are likely to cause the hyperexcitability of nociceptive neurons and pain hypersensitivity observed during inflammation. Proinflammatory mediator, tumor necrosis factor-α (TNF-α), is secreted during inflammation and is associated with the early onset, as well as long-lasting, inflammation-mediated increase in excitability of peripheral nociceptive neurons. Here we studied the underlying mechanisms of the rapid component of TNF-α-mediated nociceptive hyperexcitability and acute pain hypersensitivity. We showed that TNF-α leads to rapid onset, cyclooxygenase-independent pain hypersensitivity in adult rats. Furthermore, TNF-α rapidly and substantially increases nociceptive excitability in vitro, by decreasing action potential threshold, increasing neuronal gain and decreasing accommodation. We extended on previous studies entailing p38 MAPK-dependent increase in TTX-r sodium currents by showing that TNF-α via p38 MAPK leads to increased availability of TTX-r sodium channels by partial relief of voltage dependence of their slow inactivation, thereby contributing to increase in neuronal gain. Moreover, we showed that TNF-α also in a p38 MAPK-dependent manner increases persistent TTX-r current by shifting the voltage dependence of activation to a hyperpolarized direction, thus producing an increase in inward current at functionally critical subthreshold voltages. Our results suggest that rapid modulation of the gating of TTX-r sodium channels plays a major role in the mediated nociceptive hyperexcitability of TNF-α during acute inflammation and may lead to development of effective treatments for inflammatory pain, without modulating the inflammation-induced healing processes.

Pubmed
Journal: Liver international : official journal of the International Association for the Study of the Liver
October/9/2012
Abstract

OBJECTIVE

TNF-α is increased in hepatopulmonary syndrome (HPS). Pentoxifylline (PTX) mitigated experimental HPS through the inhibition of TNF-α. However, PTX has pleiotropic effects besides the inhibition of TNF-α. This study is to neutralize TNF-α with specific monoclonal antibody to TNF-α (TNF-α McAb) to investigate the effect of TNF-α on HPS.

METHODS

Hepatopulmonary syndrome was induced by common bile duct ligation (CBDL); controls were sham operated. The endpoints were 1, 2, 3, 4 and 5 weeks after surgery. (99m) Technetium-macroaggregated albumin (Tc-MAA) was to evaluate intrapulmonary arteriovenous shunts; Portal venous pressure, cardiac output and mean blood pressure (MAP) were also measured. Serum was for Alanine transaminase (ALT), endotoxin, TNF-α and nitric oxide (NO) measurements, liver for histology, lung for histology and iNOS, PI3K/Akt expression assay.

RESULTS

Portal vein pressure was significantly elevated and MAP decreased in CBDL rats. Tc-MAA was mainly located in lung and very weak in brain in sham group and mainly in brain of CBDL rats. TNF-α McAb significantly decreased the radioactivity in the brain, reduced cardiac output, increased MAP and systemic vascular resistance (SVR) in CBDL animals. Serum ALT, endotoxin, TNF-α and NO were significantly increased. TNF-α McAb significantly decreased these serum indices in CBDL rats. TNF-α McAb significantly alleviated liver damage, decreased alveolar-arterial gradient and inhibited iNOS, PI3K/Akt and p-Akt expression in lung tissue. Furthermore, TNF-α McAb significantly attenuated the inflammatory response in lung.

CONCLUSIONS

TNF-α McAb improves HPS in cirrhotic rats; this effect is likely mediated through the inhibition of TNF-α PI3K/Akt-NO pathway.

Pubmed
Journal: International journal of immunogenetics
February/25/2009
Abstract

This study attempted to establish single nucleotide polymorphism frequencies of TNF, IL6, IFNG, IL10 and TGFB1 genes among healthy individuals from South and Southeast Brazil. The sample included 108 healthy individuals from South and 106 from Southeast Brazil. Polymerase chain reaction using sequence-specific primers genotyping was performed for these gene cytokines with Cytokine Genotyping Primers (One Lambda, Canoga Park, CA, USA). Differences in genotypic and allelic frequencies between the populations were assessed by chi-square with either Yates' correction or Fisher's exact test. Our investigations showed that there were not any significant differences between these two Brazilian populations for these polymorphisms. A statistically significant difference in the distribution of alleles and genotypes for both IL6 and IL10 genes was observed between the Brazilian population and the African-derived populations. IL6-174GG genotype and allele G and IL10-819CT/-592CA genotypes are more frequent in African-derived populations than in this mixed Brazilian population, while IL10-1082GG genotype is more frequent in our population. This mixed Brazilian population is closer to those of Joinville's, Santa Catarina, and Rio de Janeiro's, Rio de Janeiro (RJ), Euro-Brazilian populations than to those of Salvador's, Bahia, and Rio de Janeiro's, RJ, African-Brazilian populations. These findings have an enormous importance for experimental design and empowering future linkage and association mapping studies of the role of cytokines in human diseases and allotransplantation outcome in Brazil.

Pubmed
Journal: Clinica chimica acta; international journal of clinical chemistry
September/14/2006
Abstract

BACKGROUND

Patients with chronic kidney disease manifest an inflammatory state in comparison to healthy individuals. Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine involved in initiation and progression of renal injury. We examined the 2-promoter region polymorphism of TNF-alpha gene G to A at -308 and at +488 sites in end-stage renal disease (ESRD) subjects.

METHODS

The TNF-alpha -308 G/A and +488 G/A polymorphisms were genotyped in 231 patients aged 36.5+/-10, and in 180 matched controls (34.96+/-11.3) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system (ARMS-PCR) method, respectively.

RESULTS

The genotypic distribution of TNF-alpha -308 and +488 were significantly different between patients and controls (P<0.001 and P<0.006), respectively. The AA genotype was more frequent in ESRD patients than controls for both the sites (42% vs. 2.8% and 17.3% vs. 2.2%), respectively. The allelic frequency of TNF-alpha A was also higher in cases than in controls for both the sites (P<0.001; OR=2.96; 95% CI=2.228-3.945 and P<0.013; OR=1.422; 95% CI=1.078-1.876). Significant difference was observed for haplotype frequency distribution between ESRD patients and controls and 'A-G#' haplotype showed >9-fold higher risk (OR=9.886, 95% CI=4.408-22.172). The two polymorphisms were in linkage disequilibrium in the control group (D'=0.8047, P<0.001).

CONCLUSIONS

Both the variants of TNF-alpha (-308 and +488) polymorphism had significant association and may thus be a strong predisposing risk factor for ESRD in a cohort of north Indian population. Further, individuals with haplotypes A-G# may be at higher risk for ESRD.

Pubmed
Journal: Infection and immunity
August/23/2012
Abstract

Osteoarticular brucellosis is the most common presentation of the active disease in humans. Loss of bone is a serious complication of localized bacterial infection of bones or the adjacent tissue, and brucellosis proved not to be the exception. The skeleton is a dynamic organ system which is constantly remodeled. Osteoblasts are responsible for the deposition of bone matrix and are thought to facilitate the calcification and mineralization of the bone matrix, and their function could be altered under infectious conditions. In this article, we describe immune mechanisms whereby Brucella abortus may invade and replicate within osteoblasts, inducing apoptosis, inhibiting mineral and organic matrix deposition, and inducing upregulation of RANKL expression. Additionally, all of these mechanisms contributed in different ways to bone loss. These processes implicate the activation of signaling pathways (mitogen-activated protein kinases [MAPK] and caspases) involved in cytokine secretion, expression of activating molecules, and cell death of osteoblasts. In addition, considering the relevance of macrophages in intracellular Brucella survival and proinflammatory cytokine secretion in response to infection, we also investigated the role of these cells as modulators of osteoblast survival, differentiation, and function. We demonstrated that supernatants from B. abortus-infected macrophages may also mediate osteoblast apoptosis and inhibit osteoblast function in a process that is dependent on the presence of tumor necrosis factor alpha (TNF-α). These results indicate that B. abortus may directly and indirectly harm osteoblast function, contributing to the bone and joint destruction observed in patients with osteoarticular complications of brucellosis.

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