Inhibition of lipopolysaccharide-stimulated TNF-α promoter activity by S-adenosylmethionine and 5′-methylthioadenosine

2004 ◽  
Vol 287 (2) ◽  
pp. G352-G362 ◽  
Author(s):  
Nary Veal ◽  
Chih-Lin Hsieh ◽  
Shigang Xiong ◽  
Jose M. Mato ◽  
Shelly Lu ◽  
...  
Keyword(s):  
Kupffer Cells ◽  
Promoter Activity ◽  
Inhibitory Effect ◽  
Transcriptional Level ◽  
Methyl Donor ◽  
Transfection Experiment ◽  
Hepatic Macrophages ◽  
Tnf Α ◽  
Potent Inhibitory Effect ◽  
Coactivator P300

S-adenosylmethionine (SAM) is the principal biological methyl donor and precursor for polyamines. SAM is known to be hepatoprotective in many liver disease models in which TNF-α is implicated. The present study investigated whether and how SAM inhibited LPS-stimulated TNF-α expression in Kupffer cells (hepatic macrophages). SAM downregulated TNF-α expression in LPS-stimulated Kupffer cells at the transcriptional level as suggested by a transfection experiment with a TNF-α promoter-reporter gene. This inhibition was not mediated through decreased NF-κB binding to four putative κB binding elements located within the promoter. The inhibited promoter activity was neither prevented by overexpression of p65 and/or its coactivator p300 nor enhanced by overexpression of coactivator-associated arginine methyltransferase-1, an enzyme that methylates p300 and inhibits a p65-p300 interaction. SAM did not lead to DNA methylation at the most common CpG target sites in the TNF-α promoter. Moreover, 5′-methylthioadenosine (MTA), which is derived from SAM but does not serve as a methyl donor, recapitulated SAM's effect with more potency. These data demonstrate that SAM inhibits TNF-α expression at the level downstream of NF-κB binding and at the level of the promoter activity via mechanisms that do not appear to involve the limited availability of p65 or p300. Furthermore, our study is the first to demonstrate a potent inhibitory effect on NF-κB promoter activity and TNF-α expression by a SAM's metabolite, MTA.

scholarly journals Inactivation of Kupffer cells by gadolinium administration prevents lipopolysaccharide-induced decrease in liver insulin-like growth factor-I and IGF-binding protein-3 gene expression

2006 ◽  
Vol 188 (3) ◽  
pp. 503-511 ◽  
Author(s):  
M Granado ◽  
A I Martín ◽  
T Priego ◽  
M A Villanúa ◽  
A López-Calderón
Keyword(s):  
Gene Expression ◽  
Kupffer Cells ◽  
Inhibitory Effect ◽  
Gadolinium Chloride ◽  
Serum Concentrations ◽  
Tnf Α ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Igfbp 3

Gram-negative bacterial infection or treatment of animals with bacterial lipopolysaccharide (LPS) induces a catabolic state with proteolysis, liver injury and an inhibition of the insulin-like growth factor-I (IGF-I) system. The purpose of this work was to elucidate the role of Kupffer cells in LPS-induced inhibition of the IGF-I/IGF-binding protein-3 (IGFBP-3) system. Adult male Wistar rats were either pretreated with the Kupffer cell inhibitor gadolinium chloride (10 mg/kg, i.v., 24 h prior to LPS exposure) or saline vehicle. Rats received two i.p. injections of 1 mg/kg LPS (at 17:30 and 08:30 h the following day) and were killed 4 h after the second injection. LPS administration induced a significant decrease in body weight and in serum concentrations of IGF-I and IGFBP-3 (P < 0.01), as well as in their gene expression in the liver. LPS-injected rats had increased serum concentrations of ACTH, corticosterone (P < 0.05), tumour necrosis factor-α (TNF-α) and nitrites (P < 0.01). Pretreatment of the animals with gadolinium chloride blocked the inhibitory effect of LPS on body weight, and on serum concentrations of IGF-I, IGFBP-3 and nitrites, as well as growth hormone receptor (GHR), IGF-I and IGFBP-3 gene expression in the liver. In contrast, gadolinium chloride administration did not modify the stimulatory effect of LPS on serum concentrations of ACTH, corticosterone and TNF-α. These results suggest that Kupffer cells are important mediators in the inhibitory effect of LPS on GHR, IGF-I and IGFBP-3 gene expression in the liver, leading to a decrease in serum concentrations of IGF-I and IGFBP-3.

Iron activates NF-κB in Kupffer cells

2002 ◽  
Vol 283 (3) ◽  
pp. G719-G726 ◽  
Author(s):  
Hongyun She ◽  
Shigang Xiong ◽  
Min Lin ◽  
Ebrahim Zandi ◽  
Cecilia Giulivi ◽  
...  
Keyword(s):  
Liver Injury ◽  
Kupffer Cells ◽  
Promoter Activity ◽  
Redox Status ◽  
Dependent Manner ◽  
Activator Protein 1 ◽  
Paramagnetic Resonance ◽  
Tnf Α ◽  
Electron Paramagnetic ◽  
Necrosis Factor

10.1152/ajpgi.00108. 2002.— Iron exacerbates various types of liver injury in which nuclear factor (NF)-κB-driven genes are implicated. This study tested a hypothesis that iron directly elicits the signaling required for activation of NF-κB and stimulation of tumor necrosis factor (TNF)-α gene expression in Kupffer cells. Addition of Fe2+ but not Fe3+ (∼5–50 μM) to cultured rat Kupffer cells increased TNF-α release and TNF-α promoter activity in a NF-κB-dependent manner. Cu+ but not Cu2+ stimulated TNF-α protein release and promoter activity but with less potency. Fe2+ caused a disappearance of the cytosolic inhibitor κBα, a concomitant increase in nuclear p65 protein, and increased DNA binding of p50/p50 and p65/p50 without affecting activator protein-1 binding. Addition of Fe2+ to the cells resulted in an increase in electron paramagnetic resonance-detectable ·OH peaking at 15 min, preceding activation of NF-κB but coinciding with activation of inhibitor κB kinase (IKK) but not c-Jun NH2-terminal kinase. In conclusion, Fe2+ serves as a direct agonist to activate IKK, NF-κB, and TNF-α promoter activity and to induce the release of TNF-α protein by cultured Kupffer cells in a redox status-dependent manner. We propose that this finding offers a molecular basis for iron-mediated accentuation of TNF-α-dependent liver injury.

scholarly journals Repression of transforming-growth-factor-β-mediated transcription by nuclear factor κB

2000 ◽  
Vol 348 (3) ◽  
pp. 591-596 ◽  
Author(s):  
Raman P. NAGARAJAN ◽  
Feifei CHEN ◽  
Wei LI ◽  
Eva VIG ◽  
Maureen A. HARRINGTON ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Regulatory Protein ◽  
Transforming Growth Factor Β ◽  
Inhibitory Effect ◽  
Transcriptional Level ◽  
Nuclear Factor ◽  
Tnf Α ◽  
Response Expression

Activation of transforming growth factor-β (TGF-β) and activin receptors leads to phosphorylation of Sma- and Mad-related protein 2 (Smad2) and Smad3, which function as transcription factors to regulate gene expression. Smad7 is a regulatory protein which is able to inhibit TGF-β and activin signalling in a negative-feedback loop, mediated by a direct regulation by Smad3 and Smad4 via a Smad-binding element (SBE) in the Smad7 promoter. Interestingly, we found that the Smad7 promoter was also regulated by nuclear factor ĸB (NF-ĸB), a transcription factor which plays an important role in inflammation and the immune response. Expression of NF-ĸB p65 subunit was able to inhibit the Smad7 promoter activity, and this inhibition could be reversed by co-expression of IĸB, an inhibitor of NF-ĸB. In addition, the inhibitory activity of p65 was observed in a minimal promoter that contained only the Smad7 SBE and a TATA box, without any consensus NF-ĸB binding site. This inhibitory effect appeared to be common to other TGF-β- and activin-responsive promoters, since p65 also inhibited the forkhead-activin-signal-transducer-2-mediated activation of a Xenopus Mix.2 promoter, as well as the Smad3-mediated activation of 3TP-lux which contains PMA-responsive elements and a plasminogen-activator-inhibitor-1 promoter. Activation of endogenous NF-ĸB by tumour necrosis factor-α (TNF-α) was also able to inhibit the Smad7 promoter in human embryonic kidney 293 cells. In human hepatoma HepG2 cells, TNF-α was able to inhibit TGF-β- and activin-mediated transcriptional activation. Furthermore, overexpression of the transcription co-activator p300 could abrogate the inhibitory effect of NF-ĸB on the Smad7 promoter. Taken together, these data have indicated a novel mode of crosstalk between the Smad and the NF-ĸB signalling cascades at the transcriptional level by competing for a limiting pool of transcription co-activators.

UBE2L6 is Involved in Cisplatin Resistance by Regulating the Transcription of ABCB6

2020 ◽  
Vol 20 (12) ◽  
pp. 1487-1496 ◽  
Author(s):  
Midori Murakami ◽  
Hiroto Izumi ◽  
Tomoko Kurita ◽  
Chiho Koi ◽  
Yasuo Morimoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Promoter Activity ◽  
Anticancer Agent ◽  
Cisplatin Resistance ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Molecular Target ◽  
Transcriptional Level ◽  
And Control ◽  
Resistant Cells

Background: Cisplatin is an important anticancer agent in cancer chemotherapy, but when resistant cells appear, treatment becomes difficult, and the prognosis is poor. Objective: In this study, we investigated the gene expression profile in cisplatin sensitive and resistant cells, and identified the genes involved in cisplatin resistance. Methods: Comparison of gene expression profiles revealed that UBE2L6 mRNA is highly expressed in resistant cells. To elucidate whether UBE2L6 is involved in the acquisition of cisplatin resistance, UBE2L6- overexpressing cells established from cisplatin-sensitive cells and UBE2L6-silenced cells developed from cisplatin- resistant cells were generated, and the sensitivity of cisplatin was examined. Results: The sensitivity of the UBE2L6-overexpressing cells did not change compared with the control cells, but the UBE2L6-silenced cells were sensitized to cisplatin. To elucidate the mechanism of UBE2L6 in cisplatin resistance, we compared the gene expression profiles of UBE2L6-silenced cells and control cells and found that the level of ABCB6 mRNA involved in cisplatin resistance was decreased. Moreover, ABCB6 promoter activity was partially suppressed in UBE2L6-silenced cells. Conclusion: These results suggest that cisplatin-resistant cells have upregulated UBE2L6 expression and contribute to cisplatin resistance by regulating ABCB6 expression at the transcriptional level. UBE2L6 might be a molecular target that overcomes cisplatin resistance.

scholarly journals Aquatic Toxicity of Photocatalyst Nanoparticles to Green Microalgae Chlorella vulgaris

Water ◽  
2020 ◽  
Vol 13 (1) ◽  
pp. 77
Author(s):  
Cristina Adochite ◽  
Luminita Andronic
Keyword(s):  
Chlorella Vulgaris ◽  
Advanced Oxidation Process ◽  
Growth Parameters ◽  
Aquatic Toxicity ◽  
Basal Medium ◽  
Inhibitory Effect ◽  
Synthesis Methods ◽  
Potent Inhibitory Effect ◽  
Density Surface ◽  
The Impact

In the last years, nanoparticles such as TiO2, ZnO, NiO, CuO and Fe2O3 were mainly used in wastewater applications. In addition to the positive aspects concerning using nanoparticles in the advanced oxidation process of wastewater containing pollutants, the impact of these nanoparticles on the environment must also be investigated. The toxicity of nanoparticles is generally investigated by the nanomaterials’ effect on green algae, especially on Chlorella vulgaris. In this review, several aspects are reviewed: the Chlorella vulgaris culture monitoring and growth parameters, the effect of different nanoparticles on Chlorella vulgaris, the toxicity of photocatalyst nanoparticles, and the mechanism of photocatalyst during oxidative stress on the photosynthetic mechanism of Chlorella vulgaris. The Bold basal medium (BBM) is generally recognized as an excellent standard cultivation medium for Chlorella vulgaris in the known environmental conditions such as temperature in the range 20–30 °C and light intensity of around 150 μE·m2·s−1 under a 16/8 h light/dark cycle. The nanoparticles synthesis methods influence the particle size, morphology, density, surface area to generate growth inhibition and further algal deaths at the nanoparticle-dependent concentration. Moreover, the results revealed that nanoparticles caused a more potent inhibitory effect on microalgal growth and severely disrupted algal cells’ membranes.

scholarly journals Let-7a-5p regulates the inflammatory response in chronic rhinosinusitis with nasal polyps

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jianwei Zhang ◽  
Lei Han ◽  
Feng Chen
Keyword(s):  
Inflammatory Response ◽  
Chronic Rhinosinusitis ◽  
Nasal Polyps ◽  
Mapk Pathway ◽  
Inhibitory Effect ◽  
Luciferase Reporter ◽  
Western Blot Assay ◽  
Protein Levels ◽  
Tnf Α

Abstract Background Let-7a-5p is demonstrated to be a tumor inhibitor in nasopharyngeal carcinoma. However, the role of let-7a-5p in chronic rhinosinusitis with nasal polyps (CRSwNP) has not been reported. This study is designed to determine the pattern of expression and role of let-7a-5p in CRSwNP. Methods The expression level of let-7a-5p, TNF-α, IL-1β, and IL-6 in CRSwNP tissues and cells were detected by RT-qPCR. Western blot assay was carried out to measure the protein expression of the Ras-MAPK pathway. Dual luciferase reporter assay and RNA pull-down assay were used to explore the relationship between let-7a-5p and IL-6. Results Let-7a-5p was significantly downregulated in CRSwNP tissues and cells. Moreover, the mRNA expression of TNF-α, IL-1β and IL-6 was increased in CRSwNP tissues, while let-7a-5p mimic inhibited the expression of TNF-α, IL-1β and IL-6. Besides that, let-7a-5p was negatively correlated with TNF-α, IL-1β and IL-6 in CRSwNP tissues. In our study, IL-6 was found to be a target gene of let-7a-5p. Additionally, let-7-5p mimic obviously reduced the protein levels of Ras, p-Raf1, p-MEK1 and p-ERK1/2, while IL-6 overexpression destroyed the inhibitory effect of let-7a-5p on the Ras-MAPK pathway in CRSwNP. Conclusion We demonstrated that let-7a-5p/IL-6 interaction regulated the inflammatory response through the Ras-MAPK pathway in CRSwNP.

scholarly journals An Anti-Inflammatory 2,4-Cyclized-3,4-Secospongian Diterpenoid and Furanoterpene-Related Metabolites of a Marine Sponge Spongia sp. from the Red Sea

Marine Drugs ◽  
2021 ◽  
Vol 19 (1) ◽  
pp. 38
Author(s):  
Chi-Jen Tai ◽  
Chiung-Yao Huang ◽  
Atallah F. Ahmed ◽  
Raha S. Orfali ◽  
Walied M. Alarif ◽  
...  
Keyword(s):  
Red Sea ◽  
Superoxide Anion ◽  
Dermal Fibroblast ◽  
Fibroblast Cell ◽  
Inhibitory Effect ◽  
Human Dermal Fibroblast ◽  
Superoxide Anion Generation ◽  
Potent Inhibitory Effect ◽  
Anti Inflammatory ◽  
New Compounds

Chemical investigation of a Red Sea Spongia sp. led to the isolation of four new compounds, i.e., 17-dehydroxysponalactone (1), a carboxylic acid, spongiafuranic acid A (2), one hydroxamic acid, spongiafuranohydroxamic acid A (3), and a furanyl trinorsesterpenoid 16-epi-irciformonin G (4), along with three known metabolites (−)-sponalisolide B (5), 18-nor- 3,17-dihydroxy-spongia-3,13(16),14-trien-2-one (6), and cholesta-7-ene-3β,5α-diol-6-one (7). The biosynthetic pathway for the molecular skeleton of 1 and related compounds was postulated for the first time. Anti-inflammatory activity of these metabolites to inhibit superoxide anion generation and elastase release in N-formyl-methionyl-leucyl phenylalanine/cytochalasin B (fMLF/CB)-induced human neutrophil cells and cytotoxicity of these compounds toward three cancer cell lines and one human dermal fibroblast cell line were assayed. Compound 1 was found to significantly reduce the superoxide anion generation and elastase release at a concentration of 10 μM, and compound 5 was also found to display strong inhibitory activity against superoxide anion generation at the same concentration. Due to the noncytotoxic activity and the potent inhibitory effect toward the superoxide anion generation and elastase release, 1 and 5 can be considered to be promising anti-inflammatory agents.

scholarly journals Apoptotic effect of novel pyrazolone-based derivative [Cu(PMPP-SAL)(EtOH)] on HeLa cells and its mechanism

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Delizhaer Reheman ◽  
Jing Zhao ◽  
Shan Guan ◽  
Guan-Cheng Xu ◽  
Yi-Jie Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cervical Cancer ◽  
Hela Cells ◽  
Copper Complexes ◽  
Antibacterial Properties ◽  
Inhibitory Effect ◽  
Parp Cleavage ◽  
Potential Candidate ◽  
Tnf Α

Abstract Pyrazolone complexes have strong anti-tumor and antibacterial properties, but the anti-tumor mechanism of pyrazolone-based copper complexes has not been fully understood. In this study, the possible mechanism and the inhibitory effect of a novel pyrazolone-based derivative compound [Cu(PMPP-SAL)(EtOH)] on human cervical cancer cells (HeLa cells) was investigated. [Cu(PMPP-SAL)(EtOH)] effectively inhibited proliferation of HeLa cells in vitro with an IC50 value of 2.082 after treatment for 72 h. Cell cycle analysis showed apoptosis was induced by blocking the cell cycle in the S phase. [Cu(PMPP-SAL)(EtOH)] promoted the loss of mitochondrial membrane potential, release of cytochrome c, PARP cleavage, and activation of caspase-3/9 in HeLa cells. Additionally, [Cu(PMPP-SAL)(EtOH)] inhibited the PI3K/AKT pathway and activated the P38/MAPK, and JNK/MAPK pathways. [Cu(PMPP-SAL)(EtOH)] also inhibited the phosphorylation of Iκ-Bα in the NF-κB pathway activated by TNF-α, thus restricting the proliferation of HeLa cells which were activated by TNF-α. In conclusion, [Cu(PMPP-SAL)(EtOH)] inhibited the growth of HeLa cells and induced apoptosis possibly via the caspase-dependent mitochondria-mediated pathway. These results suggest that [Cu(PMPP-SAL)(EtOH)] can be a potential candidate for the treatment of cervical cancer.

scholarly journals Prostaglandin E2 Affects Differently the Release of Inflammatory Mediators from Resident Macrophages by LPS and Muramyl Tripeptides

1999 ◽  
Vol 8 (6) ◽  
pp. 295-303 ◽  
Author(s):  
Peter Dieter ◽  
Ute Hempel ◽  
Sabine Kamionka ◽  
Angelika Kolada ◽  
Birgit Malessa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Transcription Factors ◽  
Map Kinase ◽  
Kupffer Cells ◽  
Neutralizing Antibodies ◽  
Target Cells ◽  
Tnf Α ◽  
Extracellular Regulated Kinase ◽  
Oxide Synthase ◽  
Rapid Activation

LPS and MTP-PE (liposome-encapsulatedN-acetylmuramyl-L-alanyl-D-isoglutaminyl-L-alanine-2-:[1',2'-dipalmitoyl-sni-glycero-3-(hydroxy-phosphoryl-oxyl)] etylamide) induce in liver macrophages a synthesis and release of TNF-α, nitric oxide and prostanoids. Both agents induce an expression of mRNA's encoding TNF-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, and of corresponding proteins. LPS and MTP-PE induce a rapid activation of the extracellular regulated kinase (ERK) isoenzymes-1 and -2. Inhibition of map kinase isoenzymes leads to a decreased release of TNF-α, nitric oxide and prostaglandin (PG) E2after both agents. The transcription factors NF-κB and AP-1 are strongly activated by LPS within 30 minutes. MTP-PE induces a weak activation of both transcription factors only after 5 hours. Inhibition of NF-κB inhibits the LPS- but not the MTP-PE-induced release of TNF-α, nitric oxide and PGE2. PGE2release after LPS is higher than after MTP-PE. Exogenously added PGE2inhibits the activation of map kinase and TNF-α release by LPS, but not by MTP-PE. Release of nitric oxide after LPS and MTP-PE is enhanced after prior addition of PGE2. PGD2is without any effect. MTP-PE, but not LPS, induces a cytotoxicity of Kupffer cells against P815 tumor target cells. The MTP-PE-induced cytotoxicity is reduced by TNF-α neutralizing antibodies, indicating the involvement of TNF-α. Thus our results suggest that the different potencies of LPS and MTP-PE as immunomodulators probably result from different actions on Kupffer cells, resulting in differences in the amounts and kinetics of released TNF-α and PGE2, and that PGE2plays an important regulatory role in the action of LPS, but not in the actions of MTP-PE.

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