scholarly journals Anti-Apoptotic Effect of G-Protein-Coupled Receptor 40 Activation on Tumor Necrosis Factor-α-Induced Injury of Rat Proximal Tubular Cells

2019 ◽  
Vol 20 (14) ◽  
pp. 3386
Author(s):  
Chang Kim ◽  
Soo Joo ◽  
In Kim ◽  
Hoon-In Choi ◽  
Eun Bae ◽  
...  
Keyword(s):  
Protein Expression ◽  
Tumor Necrosis ◽  
Caspase 3 ◽  
Expression Ratio ◽  
Tnf Α ◽  
Apoptotic Effect ◽  
Proximal Tubular ◽  
Renal Tubular ◽  
G Protein Coupled ◽  
Necrosis Factor

G-protein-coupled receptor 40 (GPR40) has an anti-apoptotic effect in pancreatic β-cells. However, its role in renal tubular cell apoptosis remains unclear. To explore the role of GPR40 in renal tubular apoptosis, a two-week unilateral ureteral obstruction (UUO) mouse model was used. The protein expression of GPR40 was decreased, while the Bax/Bcl-2 protein expression ratio, the expression of tumor necrosis factor (TNF)-α mRNA, and angiotensin II type 1 receptor (AT1R) protein were increased in mice with UUO. In vitro, pretreatment of rat proximal tubular (NRK52E) cells with GW9508, a GPR40 agonist, attenuated the decreased cell viability, increased the Bax/Bcl-2 protein expression ratio, increased protein expression of cleaved caspase-3 and activated the nuclear translocation of nuclear factor-κB (NF-κB) p65 subunit induced by TNF-α treatment. TNF-α treatment significantly increased the expression of AT1R protein and the generation of reactive oxygen species (ROS), whereas GW9508 treatment markedly reversed these effects. Pretreatment with GW1100, a GPR40 antagonist, or silencing of GPR40 in NRK52E cells promoted the increased expression of the cleaved caspase-3 protein by TNF-α treatment. Our results demonstrate that decreased expression of GPR40 is associated with apoptosis via TNF-α and AT1R in the ureteral obstructed kidney. The activation of GPR40 attenuates TNF-α-induced apoptosis by inhibiting AT1R expression and ROS generation through regulation of the NF-κB signaling pathway.

scholarly journals Tumor necrosis factor-α suppresses angiotensinogen expression through formation of a p50/p50 homodimer in human renal proximal tubular cells

2010 ◽  
Vol 299 (4) ◽  
pp. C750-C759 ◽  
Author(s):  
Ryousuke Satou ◽  
Kayoko Miyata ◽  
Akemi Katsurada ◽  
L. Gabriel Navar ◽  
Hiroyuki Kobori
Keyword(s):  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Proximal Tubular Cells ◽  
Tubular Cells ◽  
Tnf Α ◽  
Proximal Tubular ◽  
Renal Proximal Tubular Cells ◽  
Renal Proximal Tubular ◽  
Factor Α ◽  
Necrosis Factor

Angiotensinogen (AGT) expression in renal proximal tubular cells (RPTCs) and intrarenal tumor necrosis factor-α (TNF-α) levels are increased in hypertension and renal diseases However, the contribution of TNF-α to AGT expression in RPTCs has not been established. Therefore, the objective of the present study was to determine influence of TNF-α on AGT expression in RPTCs. Human kidney-2 (HK-2) cells, immortalized human RPTCs, were treated with several concentrations of TNF-α up to 24 h. AGT mRNA and protein expression were evaluated by RT-PCR and ELISA, respectively. Activation of nuclear factor-κB (NF-κB) by TNF-α was evaluated by Western blot analysis, immunocytochemistry, and electrophoretic mobility shift assay (EMSA). TNF-α suppressed AGT mRNA expression in a dose- and time-dependent manner. Maximum AGT mRNA reduction was caused by 40 ng/ml of TNF-α (0.52 ± 0.09, ratio to control, at 24 h) and at 24 h (0.66 ± 0.05, ratio to control, by 10 ng/ml TNF-α). TNF-α reduced AGT protein accumulation in the medium between 8 and 24 h (0.62 ± 0.13 by 40 ng/ml TNF-α, ratio to control). TNF-α activated and induced translocalization of p50 and p65, which are NF-κB subunits. Elevated formation of p50/p65 and p50/p50 dimers by TNF-α were observed by EMSA and supershift assay. Gene silencing of p50, but not p65, attenuated the effect of TNF-α on reduction of AGT expression in RPTCs. These results indicate that TNF-α suppresses AGT expression through p50/p50 homodimer formation in human RPTCs, suggesting a possible counteracting mechanism that limits excessive intrarenal AGT production.

Role of tumor necrosis factor–α and matrix metalloproteinase–9 in blood-brain barrier disruption after peripheral thermal injury in rats

2009 ◽  
Vol 110 (6) ◽  
pp. 1218-1226 ◽  
Author(s):  
Raul Reyes ◽  
Miao Guo ◽  
Kathryn Swann ◽  
Siddharth U. Shetgeri ◽  
Shane M. Sprague ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Protein Expression ◽  
Tumor Necrosis ◽  
Thermal Injury ◽  
Fluorescein Isothiocyanate ◽  
Tnf Α ◽  
Fluorescein Isothiocyanate Dextran ◽  
Factor Α ◽  
Metalloproteinase 9 ◽  
Necrosis Factor

Object A relationship has been found between peripheral thermal injury and cerebral complications leading to injury and death. In the present study, the authors examined whether tumor necrosis factor–α (TNF-α) and matrix metalloproteinase–9 (MMP-9) play a causative role in blood-brain barrier (BBB) disruption after peripheral thermal injury. Methods Thirty-two male Sprague-Dawley rats were subjected to thermal injury. One hour later, 8 rats were injected with TNF-α neutralizing antibody, and 8 were injected with doxycycline, an inhibitor of the MMP family proteins; 16 rats did not receive any treatment. Brain tissue samples obtained 7 hours after injury in the treated animals were examined for BBB function by using fluorescein isothiocyanate–dextran and by assessing parenchymal water content. Protein expression of basement membrane components (collagen IV, laminin, and fibronectin) was quantified on Western blot analysis, and MMP-9 protein expression and enzyme activity were determined using Western blot and gelatin zymography. Thermally injured rats that did not receive treatment were killed at 3, 7, or 24 hours after injury and tested for BBB functioning at each time point. Histological analysis for basement membrane proteins was also conducted in untreated rats killed at 7 hours after injury. Results of testing in injured rats were compared with those obtained in a control group of rats that did not undergo thermal injury. Results At 7 hours after thermal injury, a significant increase in the fluorescein isothiocyanate–dextran and water content of the brain was found (p < 0.05), but BBB dysfunction was significantly decreased in the rats that received TNF-α antibody or doxycycline (p < 0.05). In addition, the components of the basal lamina were significantly decreased at 7 hours after thermal injury (p < 0.01), and there were significant increases in MMP-9 protein expression and enzyme activity (p < 0.05). The basal lamina damage was reversed by inhibition of TNF-α and MMP-9, and the increase in MMP-9 protein was reduced in the presence of doxycycline (p < 0.05). The authors found that MMP-9 enzyme activity was significantly increased after thermal injury (p < 0.01) but decreased in the presence of either TNF-α antibody or doxycycline (p < 0.01). Conclusions The dual, inhibitory activity of both TNF-α and MMP-9 in brain injury suggests that a TNF-α and MMP-9 cascade may play a key role in BBB disruption. These results offer a better understanding of the pathophysiology of burn injuries, which may open new avenues for burn treatment beyond the level of current therapies.

scholarly journals Tumor Necrosis Factor-α Promotes Survival of Opossum Kidney Cells via Cdc42-induced Phospholipase C-γ1 Activation and Actin Filament Redistribution

2004 ◽  
Vol 15 (3) ◽  
pp. 1273-1286 ◽  
Author(s):  
Evangelia A. Papakonstanti ◽  
Christos Stournaras
Keyword(s):  
Tumor Necrosis ◽  
Caspase 3 ◽  
Nuclear Factor Κb ◽  
Kidney Cells ◽  
Nuclear Factor ◽  
Signaling Mechanism ◽  
Opossum Kidney ◽  
Opossum Kidney Cells ◽  
Tnf Α ◽  
Necrosis Factor

Although the renal proximal tubular epithelial cells are targeted in a variety of inflammatory diseases of the kidney, the signaling mechanism by which tumor necrosis factor (TNF)-α exerts its effects in these cells remains unclear. Here, we report that TNF-α elicits antiapoptotic effects in opossum kidney cells and that this response is mediated via actin redistribution through a novel signaling mechanism. More specifically, we show that TNF-α prevents apoptosis by inhibiting the activity of caspase-3 and this effect depends on actin polymerization state and nuclear factor-κB activity. We also demonstrate that the signaling cascade triggered by TNF-α is governed by the phosphatidylinositol-3 kinase, Cdc42/Rac1, and phospholipase (PLC)-γ1. In this signaling cascade, Cdc42 was found to be selectively essential for PLC-γ1 activation, whereas phosphatidylinositol-3,4,5-triphosphate alone is not sufficient to activate the phospholipase. Moreover, PLC-γ1 was found to associate in vivo with the small GTPase(s). Interestingly, PLC-γ1 was observed to associate with constitutively active (CA) Cdc42V12, but not with CA Rac1V12, whereas no interaction was detected with Cdc42(T17N). The inactive Cdc42(T17N) and the PLC-γ1 inhibitor U73122 prevented actin redistribution and depolymerization, confirming that both signaling molecules are responsible for the reorganization of actin. Additionally, the actin filament stabilizer phallacidin potently blocked the nuclear translocation of nuclear factor-κB and its binding activity, resulting in abrogation of the TNF-α-induced inhibition of caspase-3. To conclude, our findings suggest that actin may play a pivotal role in the response of opossum kidney cells to TNF-α and implicate Cdc42 in directly regulating PLC-γ1 activity.

scholarly journals TIFA protein expression is associated with pulmonary arterial hypertension

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hao-Chih Chang ◽  
Tong-You Wade Wei ◽  
Pei-Yu Wu ◽  
Ming-Daw Tsai ◽  
Wen-Chung Yu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tumor Necrosis Factor ◽  
Protein Expression ◽  
Arterial Hypertension ◽  
Tumor Necrosis ◽  
Heart Catheterization ◽  
Cellular Expression ◽  
Tnf Α ◽  
Pulmonary Arterial ◽  
Necrosis Factor

AbstractTumor necrosis factor receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA), a key regulator of inflammation, may be involved in the pathogenesis of pulmonary arterial hypertension (PAH). A total of 48 PAH patients (age 50.1 ± 13.1 years, 22.9% men), 25 hypertensive subjects, and 26 healthy controls were enrolled. TIFA protein expression in peripheral blood mononuclear cells (PBMCs) and plasma interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured. Pulmonary arterial hemodynamics were derived from right heart catheterization. PAH patients had the highest expression of TIFA, TNF-α, and IL-1β. TIFA protein expression was significantly associated with IL-1β (r = 0.94; P < 0.001), TNF-α (r = 0.93; P < 0.001), mean pulmonary artery pressure (r = 0.41; P = 0.006), and pulmonary vascular resistance (r = 0.41; P = 0.007). TIFA protein expression could independently predict the presence of PAH (odds ratio [95% confidence interval per-0.1 standard deviation]: 1.72 [1.37–2.16]; P < 0.001) and outperformed echocardiographic estimation. Ex vivo silencing of TIFA protein expression in PBMCs led to the suppression of the cellular expression of IL-1β and TNF-α. IL-1β and TNF-α mediated 80.4% and 56.6% of the causal relationship between TIFA and PAH, respectively, supporting the idea that TIFA protein is involved in the pathogenesis of PAH.

scholarly journals TIFA Protein Expression is Associated with Pulmonary Arterial Hypertension

2021 ◽  
Author(s):  
Hao-Chih Chang ◽  
Tong-You Wade Wei ◽  
Pei-Yu Wu ◽  
Ming-Daw Tsai ◽  
Wen-Chung Yu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Tumor Necrosis Factor ◽  
Protein Expression ◽  
Arterial Hypertension ◽  
Tumor Necrosis ◽  
Heart Catheterization ◽  
Cellular Expression ◽  
Tnf Α ◽  
Pulmonary Arterial ◽  
Necrosis Factor

Abstract Tumor necrosis factor receptor-associated factor-interacting protein with a forkhead-associated domain (TIFA), a key regulator of inflammation, may be involved in the pathogenesis of pulmonary arterial hypertension (PAH). A total of 48 PAH patients (age 50.1±13.1 years, 22.9% men), 25 hypertensive subjects, and 26 healthy controls were enrolled. TIFA protein expression in peripheral blood mononuclear cells (PBMCs) and plasma interleukin (IL)-1β and tumor necrosis factor (TNF)-α were measured. Pulmonary arterial hemodynamics were derived from right heart catheterization. PAH patients had the highest expression of TIFA, TNF-α, and IL-1β. TIFA protein expression was significantly associated with IL-1β (r=0.94; P<0.001), TNF-α (r=0.93; P<0.001), mean pulmonary artery pressure (r=0.41; P=0.006), and pulmonary vascular resistance (r=0.41; P=0.007). TIFA protein expression could independently predict the presence of PAH (odds ratio [95% confidence interval per-0.1 standard deviation]: 1.72 [1.37-2.16]; P<0.001) and outperformed echocardiographic estimation. Ex vivo silencing of TIFA protein expression in PBMCs led to the suppression of the cellular expression of IL-1β and TNF-α. IL-1β and TNF-α mediated 80.4% and 56.6% of the causal relationship between TIFA and PAH, respectively, supporting the idea that TIFA protein is involved in the pathogenesis of PAH.

scholarly journals Stress-Induced Sensitization of Angiotensin II Hypertension Is Reversed by Blockade of Angiotensin-Converting Enzyme or Tumor Necrosis Factor-α

2019 ◽  
Vol 32 (9) ◽  
pp. 909-917 ◽  
Author(s):  
Baojian Xue ◽  
Yang Yu ◽  
Shun-Guang Wei ◽  
Terry G Beltz ◽  
Fang Guo ◽  
...  
Keyword(s):  
Drinking Water ◽  
Tumor Necrosis Factor ◽  
Angiotensin Converting Enzyme ◽  
Protein Expression ◽  
Tumor Necrosis ◽  
Ang Ii ◽  
Converting Enzyme ◽  
Tnf Α ◽  
Gene And Protein Expression ◽  
Necrosis Factor

Abstract BACKGROUND Post-traumatic stress disorder (PTSD) is characterized by a disordered stress response and associated with increased cardiovascular disease risk. The present study investigated whether angiotensin (Ang) II-elicited hypertensive response is sensitized in a model of PTSD and whether inhibition of angiotensin-converting enzyme (ACE) or tumor necrosis factor (TNF)-α prior to PTSD blocks this sensitization of Ang II hypertension. METHODS The resident–intruder paradigm was used to model PTSD. Each intruder rat (male Sprague-Dawley) was given normal drinking water or was pretreated with either an ACE inhibitor (captopril) or a TNF-α inhibitor (pentoxifylline) in the drinking water for 2 weeks. Subsequently, they were exposed to a different resident (male Long-Evans) for 2 hours on 3 days with each session separated by 1 day and then received a subcutaneous infusion of Ang II for 2 weeks. RESULTS The stressed rats had a significantly enhanced hypertensive response to the Ang II infusion (stressed Δ40.2 ± 3.9 mm Hg vs. unstressed Δ20.5 ± 4.5 mm Hg) and an upregulation of mRNA or protein expression of renin–angiotensin system (RAS) and proinflammatory cytokine (PIC) components and of a microglial marker in the lamina terminalis and hypothalamic paraventricular nucleus when compared with unstressed control rats. Both the sensitized hypertensive response and enhanced gene and protein expression were blocked by pretreatment with either ACE (Δ21.3 ± 3.9 mm Hg) or TNF-α inhibitor (Δ21.4 ± 2.6 mm Hg). CONCLUSIONS The results indicate that upregulation of the brain RAS and PICs produced by severe stress contributes to traumatic-induced sensitization of hypertensive response to Ang II, and disorders such as PTSD may predispose individuals to development of hypertension.

scholarly journals Tumor Necrosis Factor Alpha Enhances Actinobacillus actinomycetemcomitans Leukotoxin-Induced HL-60 Cell Apoptosis by Stimulating Lymphocyte Function-Associated Antigen 1 Expression†

2004 ◽  
Vol 72 (1) ◽  
pp. 269-276 ◽  
Author(s):  
Noboru Yamaguchi ◽  
Chie Kubo ◽  
Yoshikazu Masuhiro ◽  
Edward T. Lally ◽  
Toshihiko Koga ◽  
...  
Keyword(s):  
Cell Apoptosis ◽  
Tumor Necrosis ◽  
Caspase 3 ◽  
Actinobacillus Actinomycetemcomitans ◽  
Lymphocyte Function ◽  
Tnf Receptor ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT We demonstrated previously that Actinobacillus actinomycetemcomitans leukotoxin (Ltx) is greatly able to induce apoptotic signaling in cells that are positive for lymphocyte function-associated antigen 1 (LFA-1), a cell receptor of Ltx. We investigated in this study whether inflammatory cytokines can regulate apoptosis of human leukemic HL-60 cells induced by Ltx. Of the cytokines tested, tumor necrosis factor alpha (TNF-α) significantly enhanced the Ltx-induced cell apoptosis. Northern and Western blotting analyses showed that TNF-α enhanced the expression of CD11a in the cells at both the mRNA and protein levels but did not do so for CD18 expression. TNF-α also enhanced the binding of Ltx to the cells. We also observed by measuring the mitochondrial transmembrane potential and the generation of superoxide anion that the cytokine enhanced Ltx-induced apoptosis in HL-60 cells. In addition, interleukin-1β significantly enhanced Ltx-induced cell apoptosis, although the enhancing activity was lower than that of TNF-α. These stimulatory effects of both cytokines were also observed for human polymorphonuclear leukocytes. The ability of TNF-α to increase cell susceptibility to Ltx could be inhibited by preincubation of the cells with a monoclonal antibody against TNF receptor 1 but not by preincubation of the cells with a monoclonal antibody against anti-TNF receptor 2. Furthermore, the results of an assay of caspase 3 intracellular activity (PhiPhiLuxG1D2) showed that Ltx-induced caspase 3 activation was completely neutralized by CD18 antibody treatment, although significant neutralization was also observed with anti-CD11a antibody. Taken together, the results of the present study indicate that TNF-α acts as a potent stimulator of Ltx-induced HL-60 cell apoptosis via TNF receptor 1-mediated upregulation of LFA-1 expression.

scholarly journals Role of autophagy in tumor necrosis factor-α-induced apoptosis of osteoblast cells

2017 ◽  
Vol 65 (6) ◽  
pp. 1014-1020 ◽  
Author(s):  
Liwen Zheng ◽  
Wanchun Wang ◽  
Jiangdong Ni ◽  
Xinzhan Mao ◽  
Deye Song ◽  
...  
Keyword(s):  
Tumor Necrosis ◽  
Caspase 3 ◽  
Annexin V ◽  
Tnf Α ◽  
Apoptotic Marker ◽  
Mouse Osteoblast ◽  
Induced Apoptosis ◽  
Factor Α ◽  
Necrosis Factor

The aim of this study is to investigate the role of tumor necrosis factor-α (TNF-α) in apoptosis and autophagy of mouse osteoblast MC3T3-E1 cells, as well as the crosstalk between autophagy and apoptosis. Mouse osteoblast MC3T3-E1 cells were cultured in vitro and treated with 5-fluorouracil (5-FU), rapamycin, 3-methyl adenine (3-MA) and TNF-α either alone or in combination, respectively. MTT assays were used to monitor the cell viability upon different treatments. Annexin-V-FITC/propidium iodide (PI) staining was used to detect the apoptotic rate of osteoblasts. Autophagic structure and apoptotic bodies were visualized by transmission electron microscopy (TEM). Western blot analysis was performed to detect the autophagic marker LC3-II/I, p62 and apoptotic marker cleaved caspase-3. TNF-α inhibits MC3T3-E1 cell viability in a dose-dependent and time-dependent manner. Annexin-V-FITC/PI staining, coupled with TEM, showed that TNF-α induced cell apoptosis and autophagy in MC3T3-E1 cells. The autophagy inducer rapamycin ameliorated TNF-α-induced apoptosis. In contrast, 3-MA, which is an autophagy inhibitor, caused an exaggerated induction of TNF-α-induced apoptosis. TNF-α upregulated autophagy marker LC3-II/I, but downregulated p62 in osteoblasts. Combined treatment of rapamycin and TNF-α further exaggerated this effect, whereas co-treatment of 3-MA and TNF-α decreased LC3-II/I, but increased p62 compared with TNF-α alone. In addition, TNF-α caused an induction of apoptotic marker cleaved caspase-3. TNF-α-mediated induction of cleaved caspase-3 was downregulated by rapamycin, but upregulated by 3-MA, respectively. TNF-α induced both autophagy and apoptosis in osteoblasts, and upregulated autophagy protects the cell by reducing TNF-α-induced apoptosis.

#50 Gestational exposure of tumor necrosis factor-α (TNF-α) inhibitor drugs

2019 ◽  
Vol 88 ◽  
pp. 149-150 ◽  
Author(s):  
Erkoseoglu Ilknur ◽  
Kadioglu Mine ◽  
Cavusoglu Irem ◽  
Sisman Mulkiye ◽  
Aran Turhan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Gestational Exposure ◽  
Tnf Α ◽  
Factor Α ◽  
Necrosis Factor
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