Tumor necrosis factor induces neuroendocrine differentiation in small cell lung cancer cell lines

1998 ◽  
Vol 275 (2) ◽  
pp. L311-L321 ◽  
Author(s):  
Kathleen J. Haley ◽  
Kirit Patidar ◽  
Fan Zhang ◽  
Rodica L. Emanuel ◽  
Mary E. Sunday
Keyword(s):  
Cell Differentiation ◽  
Cell Lines ◽  
Nuclear Factor Κb ◽  
Neuroendocrine Cell ◽  
Acid Decarboxylase ◽  
Nuclear Factor ◽  
Small Cell Lung ◽  
Amino Acid Decarboxylase ◽  
Tnf Α ◽  
Necrosis Factor

We studied tumor necrosis factor (TNF)-α as a candidate cytokine to promote neuroendocrine cell differentiation in a nitrosamine-hyperoxia hamster lung injury model. Differential screening identified expression of the genes modulated by TNF-α preceding neuroendocrine cell differentiation. Undifferentiated small cell lung carcinoma (SCLC) cell lines NCI-H82 and NCI-H526 were treated with TNF-α for up to 2 wk. Both cell lines demonstrated rapid induction of gastrin-releasing peptide (GRP) mRNA; H82 cells also expressed aromatic-l-amino acid decarboxylase mRNA within 5 min after TNF-α was added. Nuclear translocation of nuclear factor-κB immunostaining occurred with TNF-α treatment, suggesting nuclear factor-κB involvement in the induction of GRP and/or aromatic-l-amino acid decarboxylase gene expression. We also demonstrated dense core neurosecretory granules and immunostaining for proGRP and neural cell adhesion molecule in H82 cells after 7–14 days of TNF-α treatment. We conclude that TNF-α can induce phenotypic features of neuroendocrine cell differentiation in SCLC cell lines. Similar effects of TNF-α in vivo may contribute to the neuroendocrine cell differentiation/hyperplasia associated with many chronic inflammatory pulmonary diseases.

scholarly journals JFC1 is transcriptionally activated by nuclear factor-κB and up-regulated by tumour necrosis factor α in prostate carcinoma cells

2002 ◽  
Vol 367 (3) ◽  
pp. 791-799 ◽  
Author(s):  
Sergio D. CATZ ◽  
Bernard M. BABIOR ◽  
Jennifer L. JOHNSON
Keyword(s):  
Tumour Necrosis Factor ◽  
Cell Lines ◽  
Prostate Carcinoma ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Luciferase Reporter ◽  
Nuclear Factor ◽  
Tumour Necrosis Factor Α ◽  
Factor Α ◽  
Necrosis Factor

The human promoter region of JFC1, a phosphatidylinositol 3,4,5-trisphosphate binding ATPase, was isolated by amplification of a 549bp region upstream of the jfc1 gene by the use of a double-PCR system. By primer extension analysis we mapped the transcription initiation site at nucleotide −321 relative to the translation start site. Putative regulatory elements were identified in the jfc1 TATA-less promoter, including three consensus sites for nuclear factor-κB (NF-κB). We analysed the three putative NF-κB binding sites by gel retardation and supershift assays. Each of the putative NF-κB sites interacted specifically with recombinant NF-κB p50, and the complexes co-migrated with those formed by the NF-κB consensus sequence and p50. An antibody to p50 generated a supershifted complex for these NF-κB sites. These sites formed specific complexes with nuclear proteins from tumour necrosis factor α (TNFα)-treated WEHI 231 cells, which were supershifted with antibodies against p50 and p65. The jfc1 promoter was transcriptionally active in various cell lines, as determined by luciferase reporter assays following transfection with a jfc1 promoter luciferase vector. Co-transfection with NF-κB expression vectors or stimulation with TNFα resulted in significant transactivation of the jfc1 promoter construct, although transactivation of a mutated jfc1 promoter was negligible. The expression of a dominant negative IκB (inhibitor κB) decreased basal jfc1 promoter activity. The cell lines PC-3, LNCaP and DU-145, but not Epstein—Barr virus-transformed lymphocytes, showed a dramatic increase in the expression of JFC1 after treatment with TNFα, suggesting that transcriptional activation of JFC1 by the TNFα/NF-κB pathway is significant in prostate carcinoma cell lines.

Activated Protein C Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor-α Production by Inhibiting Activation of both Nuclear Factor-κB and Activator Protein-1 in Human Monocytes

2002 ◽  
Vol 88 (08) ◽  
pp. 267-273 ◽  
Author(s):  
Mehtap Yuksel ◽  
Mitsuhiro Uchiba ◽  
Seikoh Horiuchi ◽  
Hiroaki Okabe ◽  
Kenji Okajima
Keyword(s):  
Protein C ◽  
Tumor Necrosis ◽  
Activated Protein C ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Tnf Α ◽  
Target Sites ◽  
Factor Α ◽  
Necrosis Factor

SummaryActivated protein C (APC), an important natural anticoagulant, inhibits tumor necrosis factor-α (TNF-α) production and attenuates various deleterious events induced by lipopolysaccharide (LPS), contributing thereby to a significant reduction of mortality in patients with severe sepsis. In this study, we investigated the mechanism(s) by which APC inhibits TNF-α production by LPS-stimulated human monocytes in vitro. Although APC inhibited LPS-induced TNF-α production in a concentration-dependent fashion, diisopropyl fluorophosphate-treated APC, an active-site-blocked APC, had no effect. APC inhibited both the binding of nuclear factor-κB (NF-κB) to target sites and the degradation of IκBα. APC also inhibited both the binding of activator protein-1 (AP-1) to target sites and the activation of mitogen-activated protein kinase pathways. These observations strongly suggest that APC inhibited LPS-induced TNF-α production by inhibiting the activation of both NF-κB and AP-1 and that the inhibitory activity of APC might depend on its serine protease activity. These results would at least partly explain the mechanism(s) by which APC reduces the tissue injury seen in animal models of sepsis and in patients with sepsis.

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.

Role of tumour necrosis factor receptor-1 and nuclear factor-κB in production of TNF-α-induced pro-inflammatory microparticles in endothelial cells

2014 ◽  
Vol 112 (09) ◽  
pp. 580-588 ◽  
Author(s):  
Sung Kyul Lee ◽  
Seung-Hee Yang ◽  
Il Kwon ◽  
Ok-Hee Lee ◽  
Ji Hoe Heo
Keyword(s):  
Endothelial Cells ◽  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Tumour Necrosis Factor Receptor ◽  
Dependent Manner ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Necrosis Factor

SummaryTumour necrosis factor-α (TNF-α) is upregulated in many inflammatory diseases and is also a potent agent for microparticle (MP) generation. Here, we describe an essential role of TNF-α in the production of endothelial cell-derived microparticles (EMPs) in vivo and the function of TNF-α-induced EMPs in endothelial cells. We found that TNF-α rapidly increased blood levels of EMPs in mice. Treatment of human umbilical vein endothelial cells (HUVECs) with TNF-α also induced EMP formation in a time-dependent manner. Silencing of TNF receptor (TNFR)-1 or inhibition of the nuclear factor-κB (NF-κB) in HUVECs impaired the production of TNF-α-induced EMP. Incubation of HUVECs with PKH-67-stained EMPs showed that endothelial cells readily engulfed EMPs, and the engulfed TNF-α-induced EMPs promoted the expression of pro-apoptotic molecules and upregulated intercellular adhesion molecule-1 level on the cell surface, which led to monocyte adhesion. Collectively, our findings indicate that the generation of TNF-α-induced EMPs was mediated by TNFR1 or NF-κB and that EMPs can contribute to apoptosis and inflammation of endothelial cells.

Thyrotropin modifies activation of nuclear factor κB by tumour necrosis factor α in rat thyroid cell line

2001 ◽  
Vol 354 (3) ◽  
pp. 573-579 ◽  
Author(s):  
Toyone KIKUMORI ◽  
Fukushi KAMBE ◽  
Takashi NAGAYA ◽  
Hiroomi FUNAHASHI ◽  
Hisao SEO
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Nuclear Factor Κb ◽  
Luciferase Reporter ◽  
Nuclear Factor ◽  
Tumour Necrosis Factor Α ◽  
Tnf Α ◽  
Rat Thyroid ◽  
Factor Α ◽  
Necrosis Factor

We have recently demonstrated that nuclear factor κB (NF-κB) mediates the tumour necrosis factor α (TNF-α)-dependent expression of the gene encoding interleukin 6 (IL-6) in rat thyroid FRTL-5 cells cultured in the presence of thyrotropin (TSH). In the present study we investigated how TSH is involved in the activation of NF-κB by TNF-α in the cells. Electrophoretic mobility-shift assay revealed that, in the absence of TSH, TNF-α activated a single protein–DNA complex containing the p50 subunit but not other NF-κB subunits such as p65. In contrast, two distinct protein–DNA complexes were activated in the presence of TSH: the faster-migrating complex contained only p50 subunit; the slower-migrating complex consisted of p65–p50heterodimer. This TSH effect was mimicked by forskolin and thyroid-stimulating antibodies obtained from patients with Graves's disease, suggesting that an increase in intracellular cAMP is responsible for the induction of different NF-κBs by TNF-α. A transient transfection study with a luciferase reporter gene driven by multimerized NF-κB sites demonstrated that TNF-α increased the luciferase activities only in the presence of TSH, and that this increase was inhibited by the co-transfection of mutant p65, which prevented the function of wild-type p65 in a dominant-negative manner. Accordingly, TNF-α activated the expression of the IL-6 gene in the presence of TSH but not in its absence. Although the expression of the p105 gene, another known target for NF-κB, was increased by TNF-α in the absence of TSH, the presence of TSH further increased the mRNA level. Taken together, these observations indicate that the presence of TSH is crucial for the NF-κB-mediated actions of TNF-α on thyroid follicular cells.

scholarly journals Hypoxia-inducible factor induction by tumour necrosis factor in normoxic cells requires receptor-interacting protein-dependent nuclear factor kappaB activation

2003 ◽  
Vol 370 (3) ◽  
pp. 1011-1017 ◽  
Author(s):  
YunJin JUNG ◽  
Jennifer S. ISAACS ◽  
Sunmin LEE ◽  
Jane TREPEL ◽  
Zheng-gang LIU ◽  
...  
Keyword(s):  
Tumour Necrosis Factor ◽  
Tumour Necrosis ◽  
Hypoxia Inducible Factor ◽  
Nuclear Factor Κb ◽  
Protein Stabilization ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Interacting Protein ◽  
Tnf Α ◽  
Necrosis Factor

Tumour necrosis factor α (TNF-α) binds to its receptor (TNFR1) and activates both death- and inflammation/survival-related signalling pathways. The inflammation and survival-related signalling cascade results in the activation of the transcription factor, nuclear factor κB (NF-κB) and requires recruitment of receptor-interacting protein (RIP) to TNFR1. The indispensable role of RIP in TNF-induced NF-κB activation has been demonstrated in RIP-/- mice and in cell lines derived from such mice. In the present study, we show that the TNF-α-induced accumulation of hypoxia-inducible factor 1α (HIF-1α) protein in normoxic cells is RIP-dependent. Exposing fibroblasts derived from RIP-/- mice to either cobalt or PMA resulted in an equivalent HIF-1α induction to that seen in RIP+/+ fibroblasts. In contrast, RIP-/- cells were unable to induce HIF-1α in response to TNF-α. Further, transient transfection of NIH 3T3 cells with an NF-κB super-repressor plasmid (an inhibitor of NF-κB activation) also prevented HIF-1α induction by TNF-α. Surprisingly, although HIF-1α mRNA levels remained unchanged after induction by TNF, induction of HIF-1α protein by the cytokine was completely blocked by pretreatment with the transcription inhibitors actinomycin D and 5,6-dichlorobenzimidazole riboside. Finally, TNF failed to induce both HIF-1α, made resistant to von Hippel—Lindau (VHL), and wild-type HIF-1α transfected into VHL-/- cells. These results indicate that HIF-1α induction by TNF-α in normoxic cells is mediated by protein stabilization but is nonetheless uniquely dependent on NF-κB-driven transcription. Thus the results describe a novel mechanism of HIF-1α up-regulation and they identify HIF-1α as a unique component of the NF-κB-mediated inflammatory/survival response.

scholarly journals Lutonarin from Barley Seedlings Inhibits the Lipopolysacchride-Stimulated Inflammatory Response of RAW 264.7 Macrophages by Suppressing Nuclear Factor-κB Signaling

Molecules ◽  
2021 ◽  
Vol 26 (6) ◽  
pp. 1571
Author(s):  
Ji Yeong Yang ◽  
So-Yeun Woo ◽  
Mi Ja Lee ◽  
Hyun Young Kim ◽  
Jin Hwan Lee ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Ultra Performance Liquid Chromatography ◽  
Raw 264.7 ◽  
Nuclear Factor ◽  
Raw 264.7 Macrophages ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Oxide Synthase ◽  
Necrosis Factor

Extracts from barley seedlings (BS) have known antioxidant and anti-inflammatory activities. The flavonoid lutonarin (LN) is a component of BS extract and has several known bioactivities. Here, we evaluated LN anti-inflammatory efficacy against lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Lutonarin was isolated from BS by methanol extraction and characterized by ultra-performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS/MS). Lutonarin did not reduce the viability or enhance the apoptosis rate of RAW 264.7 macrophages at concentrations up to 150 µM. Concentrations within 20–60 µM dose-dependently suppressed the LPS-induced expression, phosphorylation, and nuclear translocation of the inflammatory transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Furthermore, LN suppressed the LPS-induced upregulation of proinflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α and of the inflammatory enzyme cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Lutonarin may be a safe and effective therapeutic agent for alleviation of pathological inflammation.

Sign in / Sign up

Export Citation Format

Share Document