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 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.

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 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.

scholarly journals Major Outer Membrane Protein Omp25 of Brucella suis Is Involved in Inhibition of Tumor Necrosis Factor Alpha Production during Infection of Human Macrophages

2001 ◽  
Vol 69 (8) ◽  
pp. 4823-4830 ◽  
Author(s):  
Véronique Jubier-Maurin ◽  
Rose-Anne Boigegrain ◽  
Axel Cloeckaert ◽  
Antoine Gross ◽  
Maria-Teresa Alvarez-Martinez ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Macrophage Infection ◽  
Necrosis Factor Alpha ◽  
Human Macrophages ◽  
Tnf Α ◽  
Brucella Suis ◽  
Factor Alpha ◽  
Necrosis Factor

ABSTRACT Brucella spp. can establish themselves and cause disease in humans and animals. The mechanisms by whichBrucella spp. evade the antibacterial defenses of their host, however, remain largely unknown. We have previously reported that live brucellae failed to induce tumor necrosis factor alpha (TNF-α) production upon human macrophage infection. This inhibition is associated with a nonidentified protein that is released into culture medium. Outer membrane proteins (OMPs) of gram-negative bacteria have been shown to modulate macrophage functions, including cytokine production. Thus, we have analyzed the effects of two major OMPs (Omp25 and Omp31) of Brucella suis 1330 (wild-type [WT] B. suis) on TNF-α production. For this purpose, omp25and omp31 null mutants of B. suis(Δomp25 B. suis and Δomp31 B. suis, respectively) were constructed and analyzed for the ability to activate human macrophages to secrete TNF-α. We showed that, in contrast to WTB. suis or Δomp31 B. suis, Δomp25 B. suis induced TNF-α production when phagocytosed by human macrophages. The complementation of Δomp25 B. suis with WT omp25 (Δomp25-omp25 B. suis mutant) significantly reversed this effect: Δomp25-omp25 B. suis-infected macrophages secreted significantly less TNF-α than did macrophages infected with the Δomp25 B. suismutant. Furthermore, pretreatment of WT B. suis with an anti-Omp25 monoclonal antibody directed against an epitope exposed at the surface of the bacteria resulted in substancial TNF-α production during macrophage infection. These observations demonstrated that Omp25 of B. suis is involved in the negative regulation of TNF-α production upon infection of human macrophages.

scholarly journals Gamma Interferon and Lipopolysaccharide Interact at the Level of Transcription To Induce Tumor Necrosis Factor Alpha Expression

2001 ◽  
Vol 69 (5) ◽  
pp. 2847-2852 ◽  
Author(s):  
Julia Y. Lee ◽  
Kathleen E. Sullivan
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Gamma Interferon ◽  
Necrosis Factor Alpha ◽  
Rnase Protection ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Lipopolysaccharide (LPS) is a very potent inducer of tumor necrosis factor alpha (TNF-α) expression from monocytes and macrophages. Another inflammatory cytokine, gamma interferon (IFN-γ), can potentiate the effects of LPS, but the mechanism is not thoroughly understood. Previous reports emphasized the ability of IFN-γ to upregulate CD14 expression (the receptor for LPS), and nearly all studies have utilized sequential stimulation with IFN-γ followed by LPS to exploit this phenomenon. This study demonstrates that IFN-γ can upregulate the effect of LPS at the level of transcription. Human monoblastic Mono-Mac-6 cells produced up to threefold-greater levels of TNF-α when simultaneously stimulated with LPS and IFN-γ compared to treatment with LPS alone. RNase protection studies showed a similar increase in RNA beginning as early as within 30 min. The synthesis of TNF-α mRNA in IFN-γ- and LPS-treated Mono-Mac-6 cells was also temporally prolonged even though the message turnover rate was identical to that seen in LPS stimulated cells. The modulatory effect of IFN-γ may be mediated by Jak2.

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