scholarly journals Infection of Human Fallopian Tube Epithelial Cells with Neisseria gonorrhoeae Protects Cells from Tumor Necrosis Factor Alpha-Induced Apoptosis

2006 ◽  
Vol 74 (6) ◽  
pp. 3643-3650 ◽  
Author(s):  
Priscilla Morales ◽  
Paz Reyes ◽  
Macarena Vargas ◽  
Miguel Rios ◽  
Mónica Imarai ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Epithelial Cells ◽  
Neisseria Gonorrhoeae ◽  
Tumor Necrosis ◽  
Gonococcal Infection ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT Following infection with Neisseria gonorrhoeae, bacteria may ascend into the Fallopian tubes (FT) and induce salpingitis, a major cause of infertility. In the FT, interactions between mucosal epithelial cells and gonococci are pivotal events in the pathogen's infection cycle and the inflammatory response. In the current study, primary FT epithelial cells were infected in vitro with different multiplicities of infection (MOI) of Pil+ Opa+ gonococci. Bacteria showed a dose-dependent association with cells and induced the secretion of tumor necrosis factor alpha (TNF-α). A significant finding was that gonococcal infection (MOI = 1) induced apoptosis in approximately 30% of cells, whereas increasing numbers of bacteria (MOI = 10 to 100) did not induce apoptosis. Apoptosis was observed in only 11% of cells with associated bacteria, whereas >84% of cells with no adherent bacteria were apoptotic. TNF-α was a key contributor to apoptosis, since (i) culture supernatants from cells infected with gonococci (MOI = 1) induced apoptosis in naïve cultures, suggesting that a soluble factor was responsible; (ii) gonococcal infection-induced apoptosis was inhibited with anti-TNF-α antibodies; and (iii) the addition of exogenous TNF-α induced apoptosis, which was inhibited by the presence of increasing numbers of bacteria (MOI = 10 to 100). These data suggest that TNF-α-mediated apoptosis of FT epithelial cells is likely a primary host defense mechanism to prevent pathogen colonization. However, epithelial cell-associated gonococci have evolved a mechanism to protect the cells from undergoing TNF-α-mediated apoptosis, and this modulation of the host innate response may contribute to establishment of infection. Understanding the antiapoptotic mechanisms used by Neisseria gonorrhoeae will inform the pathogenesis of salpingitis and could suggest new intervention strategies for prevention and treatment of the disease.

scholarly journals Tumor Necrosis Factor Alpha-Induced Apoptosis Requires p73 and c-ABL Activation Downstream of RB Degradation

2004 ◽  
Vol 24 (10) ◽  
pp. 4438-4447 ◽  
Author(s):  
B. Nelson Chau ◽  
Tung-Ti Chen ◽  
Yisong Y. Wan ◽  
James DeGregori ◽  
Jean Y. J. Wang
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Wild Type ◽  
Necrosis Factor Alpha ◽  
Abl Tyrosine Kinase ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT The retinoblastoma protein (RB) suppresses cell proliferation and apoptosis. We have previously shown that RB degradation is required for tumor necrosis factor alpha (TNF-α) to induce apoptosis. We show here the identification of two apoptotic effectors, i.e., c-ABL tyrosine kinase and p73, which are activated by TNF-α following RB degradation. In cells expressing a degradation-resistant RB protein (RB-MI), TNF-α does not activate c-ABL. RB-MI also inhibits TNF-α-mediated activation of p73. Genetic deletion and pharmacological inhibition of c-ABL or p73 diminish the apoptotic response to TNF-α in human cell lines and mouse fibroblasts. Thymocytes isolated from RbMI/MI , Abl −/−, or p73 −/− mice are resistant to TNF-α-induced apoptosis compared to their wild-type counterparts. This is in contrast to p53 −/− thymocytes, which exhibit a wild-type level of apoptosis in response to TNF-α. Thus, c-ABL and p73 contribute to apoptosis induced by TNF-α, in addition to their role in promoting DNA damage-associated cell death.

scholarly journals Ammonia as an Accelerator of Tumor Necrosis Factor Alpha-Induced Apoptosis of Gastric Epithelial Cells inHelicobacter pylori Infection

2001 ◽  
Vol 69 (2) ◽  
pp. 816-821 ◽  
Author(s):  
Muneki Igarashi ◽  
Yukie Kitada ◽  
Hironori Yoshiyama ◽  
Atsushi Takagi ◽  
Takeshi Miwa ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Significant Degree ◽  
Gastric Epithelial Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
H Pylori ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT The mechanism by which Helicobacter pylori induces apoptosis remains unclear. In a previous study using biopsy samples, we found a significant correlation between the urease activity of anH. pylori strain and the apoptosis level induced by this strain. Therefore, in this study, we investigated whether urease and/or the ammonia generated by urease can induce apoptosis. Human gastric epithelial cell lines were cocultured with H. pylori, and the levels of apoptosis and ammonia production were measured. The medium was supplemented (or not supplemented) with urea and cytokines. While a large amount of ammonia (>30 mM) accumulated in the coculture containing urease-positive H. pylori and urea, no significant degree of apoptosis occurred. In the presence of tumor necrosis factor alpha (TNF-α), however, a marked acceleration of apoptosis was found in this coculture. Such enhancement of apoptosis was also induced by the addition of 4 to 8 mM ammonia to the cell culture without either H. pylori or urea but containing TNF-α. These results suggested that ammonia accelerates cytokine-induced apoptosis in gastric epithelial cells, while ammonia or urease molecules alone are unable to induce a significant degree of apoptosis.

scholarly journals Live Lactobacillus reuteri Is Essential for the Inhibitory Effect on Tumor Necrosis Factor Alpha-Induced Interleukin-8 Expression

2004 ◽  
Vol 72 (9) ◽  
pp. 5308-5314 ◽  
Author(s):  
Donglai Ma ◽  
Paul Forsythe ◽  
John Bienenstock
Keyword(s):  
Tumor Necrosis Factor ◽  
Epithelial Cells ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Lactobacillus Reuteri ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Anti Inflammatory ◽  
Necrosis Factor

ABSTRACT The mechanism of the apparent anti-inflammatory action of probiotic organisms is unclear. Lactobacillus reuteri is effective in inhibiting colitis in interleukin-10 (IL-10)-deficient mice. Nerve growth factor (NGF), in addition to its activity on neuronal cell growth, has significant anti-inflammatory effects in several experimental systems in vitro and in vivo, including a model of colitis. Our experiments were designed to explore the mechanism of effect of L. reuteri in the human epithelial cell lines T84 and HT29 on cytokine and NGF synthesis and IL-8 response to tumor necrosis factor alpha (TNF-α). Epithelial cells were cultured for various times with live and killed L. reuteri and examined by reverse transcription-PCR for NGF, IL-10, and TNF-α-induced IL-8 expression. An enzyme-linked immunosorbent assay was used to quantitate intracellular IL-8 and secreted product. Western blotting and confocal microscopy were used to determine the effects on IκB and NF-κB, respectively. Live but not heat-killed or gamma-irradiated L. reuteri upregulated NGF and dose dependently inhibited constitutive synthesis by T84 and HT29 cells of IL-8 and that induced by TNF-α in terms of mRNA and intracellular and secreted protein. Similarly, L. reuteri inhibited IL-8 synthesis induced by Salmonella enterica serovar Typhimurium. L. reuteri required preincubation and adherence for effect, inhibited translocation of NF-κB to the nuclei of HeLa cells, and prevented degradation of IκB. Neither cellular lysates nor media supernatants had any effect on TNF-α-induced IL-8. The conclusion is that L. reuteri has potent direct anti-inflammatory activity on human epithelial cells, which is likely to be related to the activity of ingested probiotics. L. reuteri also upregulates an unusual anti-inflammatory molecule, NGF, and inhibits NF-κB translocation to the nucleus.

scholarly journals CCL20/Macrophage Inflammatory Protein 3α and Tumor Necrosis Factor Alpha Production by Primary Uterine Epithelial Cells in Response to Treatment with Lipopolysaccharide or Pam3Cys

2005 ◽  
Vol 73 (1) ◽  
pp. 476-484 ◽  
Author(s):  
Mardi A. Crane-Godreau ◽  
Charles R. Wira
Keyword(s):  
Tumor Necrosis Factor ◽  
Epithelial Cells ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Inflammatory Protein ◽  
Tnf Α ◽  
Factor Alpha ◽  
Macrophage Inflammatory Protein ◽  
Necrosis Factor

ABSTRACT Having previously shown that CCL20/macrophage inflammatory protein 3α and tumor necrosis factor alpha (TNF-α) are released by polarized primary rat uterine epithelial cells (UEC) in response to Escherichia coli but not to Lactobacillus rhamnosus, we sought to determine if epithelial cells are responsive to pathogen-associated molecular patterns (PAMP), including lipopolysaccharide (LPS), lipoteichoic acid (LTA), and Pam3Cys, a bacterial lipoprotein analog. Epithelial cells were grown to confluence on Nunc cell culture inserts prior to apical treatment with PAMPs. In response to LPS, LTA, and Pam3Cys (EMC Microcollection GmbH, Tübingen, Germany), CCL20 levels increased (4- to 10-fold) while PAMPs caused increased TNF-α (1- to 4-fold) in the medium collected after 24 h of incubation. Both apical and basolateral secretion of CCL20 and TNF-α increased in response to PAMPs, but treatments had no effect on cell viability and integrity, as measured by transepithelial resistance. Time course studies of CCL20 and TNF-α release in response to Pam3Cys and LPS indicated that CCL20 release peaked between 2 and 4 h after treatment, whereas TNF-α release was gradual over the length of the incubation. Freeze-thaw and cell lysis experiments, along with actinomycin D studies, suggested that CCL20 and TNF-α are synthesized in response to PAMP stimulation. Taken together, these studies demonstrate that E. coli and selected PAMPs have direct effects on the production of CCL20 and TNF-α without affecting cell integrity. Since CCL20 is known to be both chemotactic and antimicrobial, the increase in apical and basolateral release by UEC in response to PAMPs suggests a new mechanism of innate immune protection in the female reproductive tract.

scholarly journals Role of Cytochrome c in Apoptosis: Increased Sensitivity to Tumor Necrosis Factor Alpha Is Associated with Respiratory Defects but Not with Lack of Cytochrome c Release

2007 ◽  
Vol 27 (5) ◽  
pp. 1771-1783 ◽  
Author(s):  
Uma D. Vempati ◽  
Francisca Diaz ◽  
Antoni Barrientos ◽  
Sonoko Narisawa ◽  
Abdul M. Mian ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Oxidative Phosphorylation ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Increased Sensitivity ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT Although the role of cytochrome c in apoptosis is well established, details of its participation in signaling pathways in vivo are not completely understood. The knockout for the somatic isoform of cytochrome c caused embryonic lethality in mice, but derived embryonic fibroblasts were shown to be resistant to apoptosis induced by agents known to trigger the intrinsic apoptotic pathway. In contrast, these cells were reported to be hypersensitive to tumor necrosis factor alpha (TNF-α)-induced apoptosis, which signals through the extrinsic pathway. Surprisingly, we found that this cell line (CRL 2613) respired at close to normal levels because of an aberrant activation of a testis isoform of cytochrome c, which, albeit expressed at low levels, was able to replace the somatic isoform for respiration and apoptosis. To produce a bona fide cytochrome c knockout, we developed a mouse knockout for both the testis and somatic isoforms of cytochrome c. The mouse was made viable by the introduction of a ubiquitously expressed cytochrome c transgene flanked by loxP sites. Lung fibroblasts in which the transgene was deleted showed no cytochrome c expression, no respiration, and resistance to agents that activate the intrinsic and to a lesser but significant extent also the extrinsic pathways. Comparison of these cells with lines with a defective oxidative phosphorylation system showed that cells with defective respiration have increased sensitivity to TNF-α-induced apoptosis, but this process was still amplified by cytochrome c. These studies underscore the importance of oxidative phosphorylation and apoptosome function to both the intrinsic and extrinsic apoptotic pathways.

scholarly journals Effects of Estradiol on Lipopolysaccharide and Pam3Cys Stimulation of CCL20/Macrophage Inflammatory Protein 3 Alpha and Tumor Necrosis Factor Alpha Production by Uterine Epithelial Cells in Culture

2005 ◽  
Vol 73 (7) ◽  
pp. 4231-4237 ◽  
Author(s):  
Mardi A. Crane-Godreau ◽  
Charles R. Wira
Keyword(s):  
Tumor Necrosis Factor ◽  
Epithelial Cells ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Ici 182,780 ◽  
Inflammatory Protein ◽  
Tnf Α ◽  
Factor Alpha ◽  
Macrophage Inflammatory Protein ◽  
Necrosis Factor

ABSTRACT We have previously demonstrated that rat uterine epithelial cells (UEC) produce CCL20/macrophage inflammatory protein 3 alpha (MIP3α) and tumor necrosis factor alpha (TNF-α) in response to live and heat-killed Escherichia coli and to the pathogen-associated molecular patterns (PAMP) lipopolysaccharide (LPS) and Pam3Cys. To determine whether estradiol (E2) modulates PAMP-induced CCL20/MIP3α and TNF-α secretion, primary cultures of rat UEC were incubated with E2 for 24 h and then treated with LPS or Pam3Cys or not treated for an additional 12 h. E2 inhibited the constitutive secretion of TNF-α and CCL20/MIP3α into culture media. Interestingly, E2 pretreatment enhanced CCL20/MIP3α secretion due to LPS and Pam3Cys administration. In contrast, and at the same time, E2 lowered the TNF-α response to both PAMP. To determine whether estrogen receptors (ER) mediated the effects of E2, epithelial cells were incubated with E2 and/or ICI 182,780, a known ER antagonist. ICI 182,780 had no effect on E2 inhibition of constitutive TNF-α and CCL20/MIP3α secretion. In contrast, ICI 182,780 reversed the stimulatory effect of E2 on LPS- and/or Pam3Cys-induced CCL20/MIP3α secretion as well as partially reversed the inhibitory effect of E2 on TNF-α production by epithelial cells. Overall, these results indicate that E2 regulates the production of TNF-α and CCL20/MIP3α by UEC in the absence as well as presence of PAMP. Since CCL20/MIP3α has antimicrobial activity and is chemotactic for immune cells, these studies suggest that regulation of CCL20/MIP3α and TNF-α by E2 and PAMP may have profound effects on innate and adaptive immune responses to microbial challenge in the female reproductive tract.

scholarly journals Bid-Independent Mitochondrial Activation in Tumor Necrosis Factor Alpha-Induced Apoptosis and Liver Injury

2006 ◽  
Vol 27 (2) ◽  
pp. 541-553 ◽  
Author(s):  
Xiaoyun Chen ◽  
Wen-Xing Ding ◽  
Hong-Min Ni ◽  
Wentao Gao ◽  
Ying-Hong Shi ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Liver Injury ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Apoptosis Pathway ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT The death receptor apoptosis pathway is intimately connected with the mitochondrial apoptosis pathway. Bid is a BH3-only pro-death Bcl-2 family protein and is the major molecule linking the two pathways. Bid-mediated mitochondrial activation occurs early and is responsible for the prompt progress of tumor necrosis factor alpha (TNF-α)-induced apoptosis. However, in both cultured cells and animal models of TNF-α-induced injury, later-phase Bid-independent mitochondrial activation could be demonstrated. Consequently, bid-deficient mice are still susceptible to endotoxin-induced liver injury and mortality. Notably, embryonic hepatocyte apoptosis and lethality caused by TNF-α in the absence of p65relA cannot be rescued by the simultaneous deletion of bid. Further studies indicate that multiple mechanisms including reactive oxygen species, JNK, and permeability transition are critically involved in Bid-independent mitochondrial activation. Inhibition of these events suppresses TNF-α-induced mitochondrial activation and apoptosis in bid-deficient cells. These findings thus indicate that there are at least two sets of mechanisms of mitochondrial activation upon TNF-α stimulation. While the Bid-mediated mechanism is rapid and potent, the Bid-independent mechanism progresses gradually and involves multiple players. The critical involvement of Bid-independent mitochondrial activation in TNF-α-induced apoptosis demands the intervention of TNF-α-mediated tissue injury via multiple avenues.

Studies on the Role of Tumor Necrosis Factor- Alpha ( Tnf-Α ) in Hepatocytes Induced Apoptosis in Vaccinated , Schistosoma Mansoni-Challenged Mice

2015 ◽  
Vol 45 (1) ◽  
pp. 47-60 ◽  
Author(s):  
Samia E. Etewa ◽  
Naglaa F. Abd El-Aal ◽  
Sara A. Abdelrahman ◽  
Eman H. Abd El Bary ◽  
Mahmoud A. El-Shafei
Keyword(s):  
Tumor Necrosis Factor ◽  
Schistosoma Mansoni ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

scholarly journals The Absence of NF-κB-Mediated Inhibition of c-Jun N-Terminal Kinase Activation Contributes to Tumor Necrosis Factor Alpha-Induced Apoptosis

2002 ◽  
Vol 22 (24) ◽  
pp. 8571-8579 ◽  
Author(s):  
Fangming Tang ◽  
Guilin Tang ◽  
Jialing Xiang ◽  
Qing Dai ◽  
Marsha R. Rosner ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Biological Activities ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Jnk Activation ◽  
Necrosis Factor

ABSTRACT The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) regulates immune responses, inflammation, and programmed cell death (apoptosis). TNF-α exerts its biological activities by activating multiple signaling pathways, including IκB kinase (IKK), c-Jun N-terminal protein kinase (JNK), and caspases. IKK activation inhibits apoptosis through the transcription factor NF-κB, whose target genes include those that encode inhibitors of both caspases and JNK. Despite activation of the antiapoptotic IKK/NF-κB pathway, TNF-α is able to induce apoptosis in cells sensitive to it, such as human breast carcinoma MCF-7 and mouse fibroblast LM cells. The molecular mechanism underlying TNF-α-induced apoptosis is incompletely understood. Here we report that in TNF-α-sensitive cells activation of the IKK/NF-κB pathway fails to block TNF-α-induced apoptosis, although its inactivation still promotes TNF-α-induced apoptosis. Interestingly, TNF-α-induced apoptosis is suppressed by inhibition of the JNK pathway but promoted by its activation. Furthermore, activation of JNK by TNF-α was transient in TNF-α-insensitive cells but prolonged in sensitive cells. Conversion of JNK activation from prolonged to transient suppressed TNF-α-induced apoptosis. Thus, absence of NF-κB-mediated inhibition of JNK activation contributes to TNF-α-induced apoptosis.

scholarly journals Tumor Necrosis Factor Alpha-Induced Interleukin-8 Production via NF-κB and Phosphatidylinositol 3-Kinase/Akt Pathways Inhibits Cell Apoptosis in Human Hepatocytes

2002 ◽  
Vol 70 (11) ◽  
pp. 6294-6301 ◽  
Author(s):  
Yosuke Osawa ◽  
Masahito Nagaki ◽  
Yoshiko Banno ◽  
David A. Brenner ◽  
Takahiko Asano ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Growth Inhibition ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Phosphatidylinositol 3 Kinase ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Apoptosis ◽  
Necrosis Factor

ABSTRACT Tumor necrosis factor alpha (TNF-α) not only induces apoptotic signals but also causes antiapoptotic and regenerative responses in the liver. However, the molecular mechanism(s) of the latter events remains unclear. In the present study, we examined TNF-α-induced genes in Hc human normal (unsensitized) hepatocytes by cDNA microarray analysis. Interleukin-8 (IL-8) induction was the most pronounced of the upregulated genes. The IL-8 protein level was also increased. IL-8 belongs to the ELR-CXC chemokine family and appears to exert mitogenic and antiapoptotic functions in other cell systems. IL-8 expression by TNF-α was inhibited when two survival signals, nuclear factor κB (NF-κB) and phosphatidylinositol 3-kinase (PI3K)/Akt, were inhibited by a mutant form of inhibitor of NF-κB (IκB); by dominant negative (kinase-dead) Akt; or by treatment with LY 294002, an inhibitor of PI3K. TNF-α induced apoptosis in Hc cells that were sensitized by inhibition of NF-κB and PI3K activation. IL-8 administration protected mice against concanavalin A-induced hepatitis in vivo. IL-8 also rescued the sensitized Hc cells, at least in part, from TNF-α-induced apoptosis in vitro. TNF-α inhibited DNA synthesis in unsensitized Hc cells in the absence of serum. Exogenous IL-8 reversed, though anti-IL-8 neutralization antibody enhanced, growth inhibition by TNF-α. These results indicate that IL-8, the production of which is stimulated by TNF-α, inhibits apoptosis of sensitized hepatocytes and releases normal (unsensitized) hepatocytes from growth inhibition induced by TNF-α.

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