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.

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 Enhancement of Mycobacterium tuberculosis-Induced Tumor Necrosis Factor Alpha Production from Primary Human Monocytes by an Activated T-Cell Membrane-Mediated Mechanism

2001 ◽  
Vol 69 (11) ◽  
pp. 6580-6587 ◽  
Author(s):  
Jan Warwick-Davies ◽  
Amanda J. Watson ◽  
George E. Griffin ◽  
Sanjeev Krishna ◽  
Robin J. Shattock
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Human Monocytes ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Mycobacterium tuberculosis alone induces small, donor-variable amounts of tumor necrosis factor alpha (TNF-α) from primary human monocytes in vitro. However, TNF-α release is increased 5- to 500-fold when fixed activated T cells (FAT) or their isolated, unfixed membranes are added to this system. This FAT-induced synergy was at least as potent as that induced by gamma interferon (IFN-γ) at 100 U/ml. FAT-enhanced TNF-α production is at least in part transcriptionally mediated, as reflected by quantitative changes in TNF-α mRNA between 2 and 6 h poststimulation. Unlike IFN-γ-cocultured cells, FAT-treated monocytes appeared not to have enhanced TNF-α message stability, suggesting that de novo transcription may be involved in this effect. Furthermore, M. tuberculosis alone induced only minimal DNA binding of monocyte NF-κB, but cells treated with M. tuberculosis and FAT potentiated NF-κB activity more effectively. It is therefore possible that one mechanism by which FAT synergize with M. tuberculosis to stimulate TNF-α production is via NF-κB-enhanced transcription. These data strongly suggest that in the interaction of cells involved in the immune response to M. tuberculosis, T-cell stimulation of monocyte TNF-α production involves a surface membrane interaction(s) as well as soluble mediators.

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.

scholarly journals Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Production by Human Monocytes Involves the Raf-1/MEK1-MEK2/ERK1-ERK2 Pathway

1999 ◽  
Vol 67 (8) ◽  
pp. 3824-3829 ◽  
Author(s):  
Tjomme van der Bruggen ◽  
Suzanne Nijenhuis ◽  
Estia van Raaij ◽  
Jan Verhoef ◽  
B. Sweder van Asbeck
Keyword(s):  
Signal Transduction ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Human Monocytes ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Erk2 Activation ◽  
Necrosis Factor

ABSTRACT During gram-negative sepsis, human monocytes are triggered to produce large quantities of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α) in response to endotoxin (lipopolysaccharide [LPS]). Several studies have identified signal transduction pathways that are activated by LPS, including activation of nuclear factor-κB (NF-κB) and activation of mitogen-activated protein kinases (MAPKs), including ERK1 and ERK2, c-Jun N-terminal kinase, and p38. In this study, the relevance of ERK1 and ERK2 activation for LPS-induced TNF-α production by primary human monocytes has been addressed with PD-098059, which specifically blocks activation of MAPK kinase (MEK) by Raf-1. TNF-α levels in the monocyte culture supernatant, induced by 10 ng of LPS/ml, were reduced by PD-098059 (50 μM). In addition, PD-098059 also reduced TNF-α mRNA expression when cells were stimulated for 1 h with LPS. On the other hand, LPS-induced interleukin-10 (IL-10) levels in the monocyte supernatant were only slightly inhibited by PD-098059. Ro 09-2210, a recently identified MEK inhibitor, completely abrogated TNF-α levels at nanomolar concentrations. IL-10 levels also were strongly reduced. To show the efficacy of PD-098059 and Ro 09-2210, ERK1 and -2 activation was monitored by Western blotting with an antiserum that recognizes the phosphorylated (i.e., activated) forms of ERK1 and ERK2. Addition of LPS to human monocytes resulted in activation of both ERK1 and ERK2 in a time- and concentration (50% effective concentration between 1 and 10 ng of LPS/ml)-dependent manner. Activation of ERK2 was blocked by PD-098059 (50 μM), whereas ERK1 seemed to be less affected. Ro 09-2210 completely prevented LPS-induced ERK1 and ERK2 activation. LPS-induced p38 activation also was prevented by Ro 09-2210. These data further support the view that the ERK signal transduction pathway is causally involved in the synthesis of TNF-α by human monocytes stimulated with LPS.

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.

scholarly journals Comparative Analysis of Lipopolysaccharide-Induced Tumor Necrosis Factor Alpha Activity in Serum and Lethality in Mice and Rabbits Pretreated with the Staphylococcal Superantigen Toxic Shock Syndrome Toxin 1

2001 ◽  
Vol 69 (11) ◽  
pp. 7169-7172 ◽  
Author(s):  
Martin M. Dinges ◽  
Patrick M. Schlievert
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Host Susceptibility ◽  
Necrosis Factor Alpha ◽  
Lethal Effects ◽  
Tnf Α ◽  
Factor Alpha ◽  
Toxic Shock Syndrome Toxin ◽  
Necrosis Factor

ABSTRACT Host susceptibility to lipopolysaccharide (LPS) is correlated with the levels of circulating tumor necrosis factor alpha (TNF-α) that develop in response to circulating LPS. Mice are resistant, relative to rabbits, to the lethal effects of LPS. This study indicates that mice and rabbits are equally sensitive to the lethal effects of circulating TNF-α but that mice are more resistant than rabbits to the induction of circulating TNF-α by LPS.

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