• BMB Reports
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• v.38 no.4
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• pp.447-456
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• 2005

TNF-$\alpha$ plays a pivotal role in inflammation processes which are mainly regulated by endothelial cells. While TNF-$\alpha$ induces apoptosis of several cell types like tumor cells, endothelial cells are resistant to TNFa mediated cell death. The cytotoxic effects of TNF-$\alpha$ on most cells are only evident if RNA or protein synthesis is inhibited, suggesting that de novo RNA or protein synthesis protect cells from TNF-$\alpha$ cytotoxicity, presumably by NF-${\kappa}B$ mediated induction of protective genes. However, the cytoprotective genes involved in NF-${\kappa}B$ dependent endothelial cell survival have not been sufficiently identified. In the present study, the suppression subtractive hybridization (SSH) method was employed to identify rarely transcribed TNF-$\alpha$ inducible genes in human arterial endothelial cells related to cell survival and cell cycle. The TNF-$\alpha$-induced expression of the RNA binding protein $p54^{nrb}$ and the 14-3-3 protein HS1 as shown here for the first time may contribute to the TNF-$\alpha$ mediated cell protection of endothelial cells. These genes have been shown to play pivotal roles in cell survival and cell cycle control in different experimental settings. The concerted expression of these genes together with other genes related to cell protection and cell cycle like DnaJ, $p21^{cip1}$ and the ubiquitin activating enzyme E1 demonstrates the identification of new genes in the context of TNF-$\alpha$ induced gene expression patterns mediating the prosurvival effect of TNF-$\alpha$ in endothelial cells.

• Journal of Microbiology and Biotechnology
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• v.25 no.12
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• pp.2153-2159
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• 2015

Mycoplasma hyopneumoniae is known to cause porcine enzootic pneumonia (EP), an important disease in swine production. The objective of this study was to examine the effects of sonicated protein fractions of M. hyopneumoniae on inflammatory response and gene expression in the murine alveolar macrophage MH-S cell line. The effects of sonicated protein fractions and intact M. hyopneumoniae on the gene expression of cytokines and iNOS were assessed using RT-PCR. The Annealing Control Primer (ACP)-based PCR method was used to screen differentially expressed genes. Increased transcription of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, COX-2, and iNOS mRNA was observed after exposure to the supernatant (SPT), precipitant (PPT), and intact M. hyopneumoniae protein. A time-dependent analysis of the mRNA expression revealed an upregulation after 4 h for IL-6 and iNOS and after 12 h for IL-1β and TNF-α, for both SPT and PPT; the fold change in COX-2 expression was less. A dose- and time-dependent correlation was observed in nitrite (NO) production for both protein fractions; however, there was no significant difference between the effects of the two protein fractions. In a differential gene analysis, PCR revealed differential expression for nine gene bands after 3 h of stimulation — only one gene was downregulated, while the remaining eight were upregulated. The results of this study provide insights that help improve our understanding of the mechanisms underlying the pathogenesis of and macrophage defenses against M. hyopneumoniae assault, and suggest targets for future studies on therapeutic interventions for M. hyopneumoniae infections.

• Archives of Pharmacal Research
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• v.26 no.5
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• pp.375-382
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• 2003

Effects of ginsenosides on nitric oxide (NO) production induced by lipopolysaccharide plus TNF-$\alpha$ (LNT) were examined in C6 rat glioma cells. Among several ginsenosides, ginsenoside Rd showed a complete inhibition against LNT-induced NO production. Ginsenoside Rd attenuated LNT-induced increased phosphorylation of ERK. Among several immediate early gene products, only Jun Band Fra-1 protein levels were increased by LNT, and ginsenoside Rd attenuated Jun Band Fra-1 protein levels induced by LNT. Furthermore, LNT increased AP-1 DNA binding activities, which were partially inhibited by ginsenoside Rd. Our results suggest that ginsenoside Rd exerts an inhibitory action against NO production via blocking phosphorylation of ERK, in turn, suppressing immediate early gene products such as Jun Band Fra-1 in C6 glioma cells.

• The Korean Journal of Physiology and Pharmacology
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• v.6 no.6
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• pp.319-325
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• 2002

The induction of interleukin-6 (IL-6) using combined proinflammatory agents $(LPS/IFN-{\gamma}\;or\;TNF-{\alpha}/IFN-{\gamma})$ was studied in relation to p38 mitogen-activated protein kinase (MAPK) and $NF-{\kappa}B$ transcriptional factor in primary neonatal cardiomyocytes. When added to cultures of cardiomyocytes, the combined agents $(LPS/IFN-[\gamma}\;or\;TNF-{\alpha}/IFN-{\gamma})$ had stimulatory effect on the production of IL-6 and the elevation was significantly reduced by SB203580, a specific p38 MAPK inhibitor. SB203580 inhibited protein production and gene expression of IL-6 in a concentration-dependent manner. In this study, $IFN-{\gamma}$ enhancement of $TNF-{\alpha}-induced\;NF-{\kappa}B$ binding affinity as well as p38 MAP kinase activation was observed. However, a specific inhibitor of p38 MAPK, SB203580, had no effect on $TNF-{\alpha}/IFN-{\gamma}\;or\;LPS/IFN-{\gamma}-induced\;NF-{\kappa}B$ activation. This study strongly suggests that these pathways about $TNF-{\alpha}/IFN-{\gamma}$ or $LPS/IFN-{\gamma}-activated$ IL-6 release can be primarily dissociated in primary neonatal cardiomyocytes.

• Applied Microscopy
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• v.48 no.3
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• pp.62-72
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• 2018

This study investigated the anti-obesity effect of a pear (Fructus Pyri Pyrifoliae) extract fermented by lactic-acid bacteria on obesity induced by a high-fat diet in rats. Body-weight measurement, blood analysis, and light microscope observation of adipose tissue in liver and epididymis were conducted after 8 weeks. Gene expression of leptin, adiponectin, and tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$) in liver cells were also investigated. Compared to CON, PFA and PFB showed 8% weight reduction along with weight reduction of adipose tissue in liver and epididymis. Observing the microstructure of liver cells showed that lipid droplets were smaller in PFA and PFB than in CON. We confirmed that Fructus Pyri Pyrifoliae extract fermented by lactic-acid bacteria can affect gene expression of leptin, adiponectin, and $TNF-{\alpha}$ in liver cells, showing an obesity treatment effect. From the results above, it was observed that weight gain from increased gene expression in adipose cells as well as from the increased proportion of adipose cells caused by a high-fat diet can be statistically significantly reduced by taking Fructus Pyri Pyrifoliae extract fermented by lactic-acid bacteria. Therefore, Fructus Pyri Pyrifoliae extract fermented by lactic-acid bacteria can be effective for preventing and treating obesity by reducing weight and adipose cells.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.3923-3927
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• 2016

Infection with the hepatitis C virus is a major public health concern which can lead to carcinoma and liver failure. It has been shown that single nucleotide polymorphisms can affect the level of gene activity of tumor necrosis factor (TNF) which has an important role, especially in viral infections which can lead to apaptosis of infected hepatocellular cells. We investigated the impact of three possible genotypes for rs1800629 or A/G single nucleotide polymorphism located downstream of $TNF{\alpha}$ gene promoter in groups of control (n=76) and chronic hepatitis C patients (n=89) focusing on the response to treatment among sensitive and resistant groups. Genomic DNA was extracted from $500{\mu}l$ prepheral whole blood and PCR and RFLP were used to amplify the region of interest and genotyping. With statistical analyzes a p-value <0.05 was considered meaningful. There was no significant difference in distribution of possible three genotypes among healthy individuals and patients (P=0.906, OR=1.194, CI=0.063-22.790). However, the frequency of G allele was higher in patients whereas A allele was more common among healthy individuals (p<0.0001). Further studies with more samples seem to be necessary.

• Biomedical Science Letters
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• v.19 no.1
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• pp.1-8
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• 2013

Parkin is known to be a tumor suppressor protein. Previously, we determined that parkin expression restores susceptibility to TNF-${\alpha}$-induced death of HeLa cells, a human cervical cancer cell line resistant to TNF-${\alpha}$-induced cell death. MMP-3 is a zinc-dependent protease recently reported to activate intracellular apoptotic signaling. In this study we examined the regulation of MMP-3 expression by parkin in TNF-${\alpha}$-treated HeLa cells. Furthermore, we investigated the signaling pathway involved in parkin-induced expression of MMP-3. We found that HeLa cells exhibit low levels of MMP-3 but is induced after introduction of the parkin gene into HeLa cells. Furthermore, MMP-3 expression increased further when parkin expressing cells were treated with TNF-${\alpha}$. Using chemical inhibitors of cell signaling pathways, we found that MEK-1 (PD98059), PI3K (LY294002), p38 MAPK (SB203580), and JNK inhibitors alleviated parkin-induced up-regulation of MMP-3. Finally, we show that TNF-${\alpha}$-induced cell death in parkin expressing cells is inhibited by using a MMP-3 inhibitor. These results suggest that parkin expression induces prolonged expression of MMP-3 via MEK-1, PI3K, MAPK, and JNK pathway in HeLa cells allowing the HeLa cells to become sensitive to TNF-${\alpha}$-induced cell death. These results implicate a role of MMP-3 in parkin-induced cell death in TNF-${\alpha}$ treated HeLa cells.

• Neonatal Medicine
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• v.18 no.1
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• pp.42-48
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• 2011

Purpose: Several factors including prolonged inflammatory response are thought to contribute to the pathogenesis of bronchopulmonary dysplasia (BPD). The clinical findings can be explained by an increased production of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-$\alpha$ ). We investigated the relationship between susceptibility to BPD and TNF-$\alpha$ promoter polymorphisms to identify genetic factors of the disease. Methods: Thirty-eight preterm infants who had developed BPD and 55 controlled infants with a birth weight <1,500 g were analyzed for TNF-$\alpha$ genotypes. The alleles of five promoter sites (-1031/-863/-857/-308/-238) of TNF-$\alpha$ gene were determined using $Taqman^{(R)}$-based allelic discrimination assays. Results: Gestational age ($27^{+5}{\pm}2^{+0}$ wk vs. $29^{+2}{\pm}1^{+4}$ wk, P<0.0001) and birth weight (990${\pm}$270 g vs. 1,220${\pm}$230 g, P<0.0001) were lower in the BPD group compared to the control group. The incidence of respiratory distress syndrome (71.1% vs. 49.1%, P=0.035) and patent ductus arteriosus (71.1% vs. 50.9%, P=0.052) was higher in the BPD group compared to the control group. The frequencies of the alleles and genotypes of five promoter sites (-1031/-863/-857/-308/-238) of TNF-$\alpha$ gene did not show differences between the BPD group and the control group. Conclusion: TNF-$\alpha$ promoter polymorphisms are not associated with susceptibility to BPD in Korean preterm infants.

• Pediatric Gastroenterology, Hepatology & Nutrition
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• v.10 no.1
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• pp.11-19
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• 2007

Purpose: Henoch-Sch$\"{o}$nlein purpura (HSP) is a systemic vasculitis involving the skin, joints, gastrointestinal tract, and kidney. Although the pathogenesis of HSP is still unclear, tumor necrosis factor (TNF-${\alpha}$) is regarded as an important cytokine contributing to the disease. The goal of this study was to determine the role of TNF-${\alpha}$ in the pathogenesis of HSP, and to evaluate the TNF-${\alpha}$ polymorphism for genetic susceptibility to HSP. Methods: From March 2004 to November 2005, 40 children with HSP and 32 healthy controls were included. Serum TNF-${\alpha}$ levels were measured using the ELISA method during the acute and convalescent phase of HSP. The genotypic and allelic frequencies of the TNF-${\alpha}$ gene polymorphisms at positions -308 and -238 were evaluated in patients and controls. Results: Serum TNF-${\alpha}$ levels were $23.17{\pm}11.31$ pg/mL in the acute phase of children with HSP and $10.56{\pm}5.59$ pg/mL in the convalescent phase (p=0.000). There was no significant correlation between the serum TNF-${\alpha}$ levels and the clinical scores of HSP (r=0.310, p=0.070). The genotypic frequency of the TNF-${\alpha}$ -308 polymorphism in children with HSP was not significantly different compared to healthy controls (GG 80%, GA 20% vs. GG 93.8%, GA 6.2%; p=0.094). The genotypic frequency of the TNF-${\alpha}$ -238 polymorphism in children with HSP was not significantly different (GG 97.5%, GA 2.5% vs. GG 93.8%, GA 6.3%; p=0.429). Conclusion: TNF-${\alpha}$ is assumed to be the main cytokine associated with the pathogenesis of HSP during the acute phase. However, the presence of TNF-${\alpha}$ gene polymorphisms at positions -308 and -238 did not distinguish children with HSP from normal controls.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5895-5900
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• 2014

Background: Metabolic syndrome (MS) is a cluster of complicated disorders caused by the interactive influencing factors of heredity and environment, which predisposes to many cnacers. Results from epidemic research indicate that stress is tightly related to the pathogenesis of MS and neoplasia. This paper aims to investigate the association between psychological stress and MS with respect to the tumor necrosis factor alpha (TNF${\alpha}$) and neuropeptide Y (NPY) genes in the Han and Hui ethnic groups. Methods: All subjects for this case-control study matched strict enrollment criteria (nationality, gender and age) and lived in the city of Wu Zhong of Ningxia Province in China. The enrolled group contained 102 matched pairs of Hui ethnic individuals and 98 matched pairs of Han ethnic individuals. Enrolled subjects completed the general Symptom Checklist-90 (SCL-90). The TNF${\alpha}$-308G/A variant and NPYrs16147 polymorphism were detected in case (81 males, 119 females) and control (81 males, 119 females) groups by polymerase chain reaction (PCR) amplification. Results: Nine factors of the SCL-90 were found to be statistically different (p<0.05) between case and control groups. The homozygous mutant genotype (AA) and the mutant allele (A) of the TNF${\alpha}$-308G/A gene were less frequently observed in the control population compared to the case group. The odds ratio (95% confidence interval) in "Allele" for MS was 2.28 (1.47-3.53), p=0.0001, while "OR" was 1.11 (0.83-1.47), p=0.15, for the NPYrs16147 gene polymorphism. Conclusions: Psychological stress has been positively associated with MS. A previous study from our group suggested there were differences in the level of psychological stress between Hui and Han ethnic groups. Furthermore, we found that the stress-related TNF${\alpha}$ gene was associated with MS for both Han and Hui ethnic groups. In contrast, NPY may be a possible contributor to MS and associated cancer for the Han ethnic group.