scholarly journals Bikunin Inhibits Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Induction in Macrophages

2004 ◽  
Vol 11 (6) ◽  
pp. 1140-1147 ◽  
Author(s):  
Hidenori Matsuzaki ◽  
Hiroshi Kobayashi ◽  
Tatsuo Yagyu ◽  
Kiyoshi Wakahara ◽  
Toshiharu Kondo ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Dose Dependent ◽  
Necrosis Factor

ABSTRACT Bikunin, a Kunitz-type protease inhibitor, exhibits anti-inflammatory activity in protection against cancer and inflammation. To investigate the molecular mechanism of this inhibition, we analyzed the effect of bikunin on tumor necrosis factor alpha (TNF-α) production in human peripheral mononuclear cells stimulated by lipopolysaccharide (LPS), an inflammatory inducer. Here, we show the following results. (i) LPS induced TNF-α expression in time- and dose-dependent manners through phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase pathways. (ii) Bikunin inhibits LPS-induced up-regulation of TNF-α protein expression in a dose-dependent manner, reaching 60% inhibition at the highest doses of bikunin tested (5.0 μM). (iii) Inhibition by bikunin of TNF-α induction correlates with the suppressive capacity of ERK1/2, JNK, and p38 signaling pathways, implicating repressions of at least three different signals in the inhibition. (iv) Bikunin blocks the induction of TNF-α target molecules interleukin-1β (IL-1β) and IL-6 proteins. (v) Bikunin is functional in vivo, and this glycoprotein blocks systemic TNF-α release in mice challenged with LPS. (vi) Finally, bikunin can prevent LPS-induced lethality. In conclusion, bikunin significantly inhibits LPS-induced TNF-α production, suggesting a mechanism of anti-inflammation by bikunin through control of cytokine induction during inflammation. Bikunin might be a candidate for the treatment of inflammation, including septic shock.

scholarly journals Tumor Necrosis Factor Alpha Induction of NF-κB Requires the Novel Coactivator SIMPL

2004 ◽  
Vol 24 (21) ◽  
pp. 9317-9326 ◽  
Author(s):  
Hyung-Joo Kwon ◽  
Erin Haag Breese ◽  
Eva Vig-Varga ◽  
Yong Luo ◽  
Younghee Lee ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Type I ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT A myriad of stimuli including proinflammatory cytokines, viruses, and chemical and mechanical insults activate a kinase complex composed of IκB kinase β (IKK-β), IKK-α, and IKK-γ/N, leading to changes in NF-κB-dependent gene expression. However, it is not clear how the NF-κB response is tailored to specific cellular insults. Signaling molecule that interacts with mouse pelle-like kinase (SIMPL) is a signaling component required for tumor necrosis factor alpha (TNF-α)-dependent but not interleukin-1-dependent NF-κB activation. Herein we demonstrate that nuclear localization of SIMPL is required for type I TNF receptor-induced NF-κB activity. SIMPL interacts with nuclear p65 in a TNF-α-dependent manner to promote endogenous NF-κB-dependent gene expression. The interaction between SIMPL and p65 enhances p65 transactivation activity. These data support a model in which TNF-α activation of NF-κB dependent-gene expression requires nuclear relocalization of p65 as well as nuclear relocalization of SIMPL, generating a TNF-α-specific induction of gene expression.

scholarly journals Glucocorticoids Regulate Tristetraprolin Synthesis and Posttranscriptionally Regulate Tumor Necrosis Factor Alpha Inflammatory Signaling

2006 ◽  
Vol 26 (23) ◽  
pp. 9126-9135 ◽  
Author(s):  
Kathleen Smoak ◽  
John A. Cidlowski
Keyword(s):  
Tumor Necrosis Factor ◽  
Mrna Expression ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Dependent Manner ◽  
Inflammatory Signaling ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Glucocorticoids are used to treat various inflammatory disorders, but the mechanisms underlying these actions are incompletely understood. The zinc finger protein tristetraprolin (TTP) destabilizes several proinflammatory cytokine mRNAs by binding to AU-rich elements within their 3′ untranslated regions, targeting them for degradation. Here we report that glucocorticoids induce the synthesis of TTP mRNA and protein in A549 lung epithelial cells and in rat tissues. Dexamethasone treatment leads to a sustained induction of TTP mRNA expression that is abrogated by RU486. Glucocorticoid induction of TTP mRNA is also blocked by actinomycin D but not by cycloheximide, suggesting a transcriptional mechanism which has been confirmed by transcription run-on experiments. The most widely characterized TTP-regulated gene is the AU-rich tumor necrosis factor alpha (TNF-α) gene. Dexamethasone represses TNF-α mRNA in A549 cells and decreases luciferase expression of a TNF-α 3′ untranslated region reporter plasmid in an orientation-dependent manner. Small interfering RNAs to TTP significantly prevent this effect, and a cell line stably expressing a short-hairpin RNA to TTP conclusively establishes that TTP is critical for dexamethasone inhibition of TNF-α mRNA expression. These studies provide the molecular evidence for glucocorticoid regulation of human TTP and reflect a novel inductive anti-inflammatory signaling pathway for glucocorticoids that acts via posttranscriptional mechanisms.

Erythromycin Inhibition of Lipopolysaccharide-Stimulated Tumor Necrosis Factor Alpha Production by Human Monocytes in Vitro

1992 ◽  
Vol 101 (10_suppl) ◽  
pp. 16-20 ◽  
Author(s):  
Yukiko Iino ◽  
Minoru Toriyama ◽  
Yasuhiro Natori ◽  
Koichiro Kudo ◽  
Akira Yuo
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Penicillin G ◽  
Dependent Manner ◽  
Human Monocytes ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

The mechanism of clinical effectiveness of low-dose and long-term erythromycin (EM) treatment for diffuse panbronchiolitis, sinobronchial syndrome, and associated otitis media with effusion was investigated by studying the effects of EM on tumor necrosis factor alpha (TNF-α) production by cultured human monocytes stimulated with lipopolysaccharide. At concentrations of 0.1 μg/mL or more, EM inhibited TNF-α release from human monocytes stimulated by lipopolysaccharide in a dose-dependent manner. Of the other macrolides tested, roxithromycin, an EM derivative, also showed significant inhibition of TNF-α production, whereas josamycin failed to inhibit TNF-α release from monocytes. Nonmacrolidic drugs such as minocycline hydrochloride, ofloxacin, or penicillin G had no significant effect on TNF-α production. These results suggest that the clinical improvement of chronic respiratory diseases by EM may depend on the suppression of production of inflammatory cytokines such as TNF-α.

Tumor necrosis factor-alpha expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 524-531 ◽  
Author(s):  
Sarah M. Jacobs-Helber ◽  
Kwan-ho Roh ◽  
Daniel Bailey ◽  
Emmanuel N. Dessypris ◽  
John J. Ryan ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Mitogen Activated Protein Kinase ◽  
Erythroid Cells ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Murine Erythroleukemia ◽  
Necrosis Factor

Binding of erythropoietin (EPO) to its receptor (EPOR) on erythroid cells induces the activation of numerous signal transduction pathways, including the mitogen-activated protein kinase Jun-N-terminal kinase (JNK). In an effort to understand the regulation of EPO-induced proliferation and JNK activation, we have examined the role of potential autocrine factors in the proliferation of the murine erythroleukemia cell line HCD57. We report here that treatment of these cells with EPO induced the expression and secretion of tumor necrosis factor alpha (TNF-α). EPO-dependent proliferation was reduced by the addition of neutralizing antibodies to TNF-α, and exogenously added TNF-α induced proliferation of HCD57 cells. EPO also could induce TNF-α expression in BAF3 and DA3 myeloid cells ectopically expressing EPOR. Addition of TNF-α activated JNK in HCD57 cells, and the activity of JNK was partially inhibited by addition of a TNF-α neutralizing antibody. Primary human and murine erythroid progenitors expressed TNF-α in either an EPO-dependent or constitutive manner. However, TNF-α had an inhibitory effect on both immature primary human and murine cells, suggestive that the proliferative effects of TNF-α may be limited to erythroleukemic cells. This study suggests a novel role for autocrine TNF-α expression in the proliferation of erythroleukemia cells that is distinct from the effect of TNF-α in normal erythropoiesis.

Pleural mesothelial cell response to inflammation: tumor necrosis factor-induced mitogenesis and collagen synthesis

1993 ◽  
Vol 265 (4) ◽  
pp. L382-L388 ◽  
Author(s):  
M. W. Owens ◽  
S. R. Grimes
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Collagen Synthesis ◽  
Mesothelial Cell ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Dose Dependent ◽  
Necrosis Factor

This study examined the effects of tumor necrosis factor-alpha on pleural mesothelial cell proliferation and collagen synthesis, functions which may be important in the response of the pleura to injury. Tumor necrosis factor-alpha caused a significant increase in proliferation and collagen production by rat pleural mesothelial cells in vitro. Proliferation increased in a time- and dose-dependent manner, resulting in an approximate twofold increase in the uptake of [3H]thymidine relative to control. The uptake of [3H]proline into collagenase-sensitive protein increased in a dose-dependent manner for concentrations of tumor necrosis factor-alpha > or = 1.0 ng/ml. The increase in collagen production were associated with increased steady-state levels of alpha 1(I)-procollagen mRNA. These results suggest that tumor necrosis factor-alpha may have a significant effect on pleural mesothelial cell function in vivo in the setting of inflammation. Increases in pleural mesothelial cell proliferation and collagen synthesis in response to inflammatory mediators, like tumor necrosis factor-alpha, may be important in healing the pleura after injury by a variety of disease processes.

scholarly journals LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner

2015 ◽  
Vol 36 (4) ◽  
pp. 574-584 ◽  
Author(s):  
Sandy Mattijssen ◽  
Richard J. Maraia
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Rna Binding ◽  
Dependent Manner ◽  
Necrosis Factor Alpha ◽  
Transient Decrease ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

LARP4 is a protein with unknown function that independently binds to poly(A) RNA, RACK1, and the poly(A)-binding protein (PABPC1). Here, we report on its regulation. We found a conserved AU-rich element (ARE) in the human LARP4 mRNA 3′ untranslated region (UTR). This ARE, but not its antisense version or a point-mutated version, significantly decreased the stability of β-globin reporter mRNA. We found that overexpression of tristetraprolin (TTP), but not its RNA binding mutant or the other ARE-binding proteins tested, decreased cellular LARP4 levels. RNA coimmunoprecipitation showed that TTP specifically associated with LARP4 mRNAin vivo. Consistent with this, mouse LARP4 accumulated to higher levels in TTP gene knockout (KO) cells than in control cells. Stimulation of WT cells with tumor necrosis factor alpha (TNF-α), which rapidly induces TTP, robustly decreased LARP4 with a coincident time course but had no such effect on LARP4B or La protein or on LARP4 in the TTP KO cells. The TNF-α-induced TTP pulse was followed by a transient decrease in LARP4 mRNA that was quickly followed by a subsequent transient decrease in LARP4 protein. Involvement of LARP4 as a target of TNF-α–TTP regulation provides a clue as to how its functional activity may be used in a physiologic pathway.

scholarly journals Association of tumor necrosis factor-alpha -308 G/A and -238 G/A polymorphism with diabetic retinopathy: a systematic review and updated meta-analysis.

2020 ◽  
Author(s):  
Wenna Gao ◽  
Ruilin Zhu ◽  
liu yang
Keyword(s):  
Diabetic Retinopathy ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Meta Analysis ◽  
Entire Group ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Necrosis Factor

Background: Mounting evidence has suggested tumor necrosis factor-alpha (TNF-α) can promote the development of diabetic retinopathy (DR), and TNF-α gene variants may influence DR risk. However, the results are quite different. Objectives: To comprehensively address this issue, we performed the meta-analysis to evaluate the association of TNF-α-308 G/A and -238 G/A polymorphism with DR. Method: Data were retrieved in a systematic manner and analyzed using STATA Statistical Software. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Allelic and genotypic comparisons between cases and controls were evaluated. Results: For the TNF-α-308 G/A polymorphism, overall analysis suggested a marginal association with DR [the OR(95%CI) of (GA versus GG), (GA + AA) versus GG, and (A versus G) are 1.21(1.04, 1.41), 1.20(1.03, 1.39), and 1.14(1.01, 1.30), respectively]. And the subgroup analysis indicated an enhanced association among the European population. For the TNF-α-238 G/A polymorphism, there was mild correlation in the entire group [the OR(95%CI) of (GA versus GG) is 1.55(1.14,2.11) ], which was strengthened among the Asian population. Conclusion: The meta-analysis suggested that -308 A and -238 A allele in TNF-α gene potentially increased DR risk and showed a discrepancy in different ethnicities.

scholarly journals Analysis of Subcellular RNA Fractions Revealed a Transcription-Independent Effect of Tumor Necrosis Factor Alpha on Splicing, Mediated by Spt5

2016 ◽  
Vol 36 (9) ◽  
pp. 1342-1353 ◽  
Author(s):  
Gil Diamant ◽  
Tal Eisenbaum ◽  
Dena Leshkowitz ◽  
Rivka Dikstein
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Independent Effect ◽  
Necrosis Factor Alpha ◽  
Pol Ii ◽  
Tnf Α ◽  
Factor Alpha ◽  
Induced Genes ◽  
Necrosis Factor

The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) modulates the expression of many genes, primarily through activation of NF-κB. Here, we examined the global effects of the elongation factor Spt5 on nascent and mature mRNAs of TNF-α-induced cells using chromatin and cytosolic subcellular fractions. We identified several classes of TNF-α-induced genes controlled at the level of transcription, splicing, and chromatin retention. Spt5 was found to facilitate splicing and chromatin release in genes displaying high induction rates. Further analysis revealed striking effects of TNF-α on the splicing of 25% of expressed genes; the vast majority were not transcriptionally induced. Splicing enhancement of noninduced genes by TNF-α was transient and independent of NF-κB. Investigating the underlying basis, we found that Spt5 is required for the splicing facilitation of the noninduced genes. In line with this, Spt5 interacts with Sm core protein splicing factors. Furthermore, following TNF-α treatment, levels of RNA polymerase II (Pol II) but not Spt5 are reduced from the splicing-induced genes, suggesting that these genes become enriched with a Pol II-Spt5 form. Our findings revealed the Pol II-Spt5 complex as a highly competent coordinator of cotranscriptional splicing.

scholarly journals HSP70 Induction by ING Proteins Sensitizes Cells to Tumor Necrosis Factor Alpha Receptor-Mediated Apoptosis

2006 ◽  
Vol 26 (24) ◽  
pp. 9244-9255 ◽  
Author(s):  
Xiaolan Feng ◽  
Shirin Bonni ◽  
Karl Riabowol
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Kinase Inhibitor ◽  
Heat Shock Gene ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Primary Fibroblasts ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT ING proteins affect apoptosis, growth, and DNA repair by transducing stress signals such as DNA damage, binding histones, and subsequently regulating chromatin structure and p53 activity. p53 target genes, including the p21 cyclin-dependent kinase inhibitor and Bax, an inducer of apoptosis, are regulated by ING proteins. To identify additional targets downstream of p33ING1 and p32ING2, cDNA microarrays were performed on phenotypically normal human primary fibroblasts. The 0.36% of genes affected by ING proteins in primary fibroblasts were distinct from targets seen in established cells and included the HSP70 heat shock gene, whose promoter was specifically induced >10-fold. ING1-induced expression of HSP70 shifted cells from survival to a death pathway in response to tumor necrosis factor alpha (TNF-α), and p33ING1b protein showed synergy with TNF-α in inducing apoptosis, which correlated with reduced NF-κB-dependent transcription. These findings are consistent with previous reports that HSP70 promotes TNF-α-mediated apoptosis by binding I-κΒ kinase gamma and impairing NF-κB survival signaling. Induction of HSP70 required the amino terminus of ING1b but not the plant homeodomain region that was recently identified as a histone binding domain. Regulation of HSP70 gene expression by the ING tumor suppressors provides a novel link between the INGs and the stress-regulated NF-κB survival pathway important in hypoxia and angiogenesis.

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