Evidence for Common Mechanisms in the Transcriptional Control of Type II Nitric Oxide Synthase in Isolated Hepatocytes

Díaz-Guerra, María José; Velasco, Marta; Martı́n-Sanz, Paloma; Boscá, Lisardo

doi:10.1074/jbc.271.47.30114

Cited by 90 publications

(48 citation statements)

References 52 publications

(68 reference statements)

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“…30,31) Since NF-kB and AP-1 are believed to be essentially required for iNOS gene transcription, 17,32,33) we performed reporter gene analyses using NFkB and AP-1 minimal promoters. Reporter gene assays showed that 4-hydroxykobusin inhibited activation process of both NF-kB and AP-1.…”

Section: Discussionmentioning

confidence: 99%

4-Hydroxykobusin Inhibits the Induction of Nitric Oxide Synthase by Inhibiting NF-.KAPPA.B and AP-1 Activation

Pokharel

Liu

et al. 2007

Biological & Pharmaceutical Bulletin

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Section: Discussionmentioning

confidence: 99%

4-Hydroxykobusin Inhibits the Induction of Nitric Oxide Synthase by Inhibiting NF-.KAPPA.B and AP-1 Activation

Pokharel

Liu

et al. 2007

Biological & Pharmaceutical Bulletin

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“…6 Furthermore, inhibition of viral replication by NO is shown by many laboratories by using NO donors, inhibiting NO production by NOS-inhibitors, or by using iNOS knockout mice. 7 To induce iNOS messenger RNA (mRNA), activation of the transcription factor nuclear factor-B (NF-B) is essential [8][9][10][11][12] although probably not sufficient 13,14 for full iNOS induction. To induce gene transcription, NF-B must be translocated from the cytoplasm to the nucleus.…”

mentioning

confidence: 99%

Expression of inducible nitric oxide synthase in endotoxemic rat hepatocytes is dependent on the cellular glutathione status

Vos¹,

Goor²,

Tuyt³

et al. 1999

Hepatology

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The inducible nitric oxide synthase (iNOS) promoter contains nuclear factor B (NF-B) binding sites. NF-B activation is determined, in part, by the intracellular redox status. The aim of this study was to determine the importance of the cellular glutathione status in relation to NF-B activation and iNOS expression in hepatocytes in vivo and in vitro. For in vivo experiments, rats were injected with endotoxin and sacrificed 6 hours later. Glutathione was depleted by diethylmaleate. For in vitro experiments, cultured hepatocytes from untreated rats were exposed to a cytokine mixture. Glutathione levels were depleted by diethylmaleate and restored by N-acetylcysteine. Nitric oxide radicals (NO) are synthesized by the enzyme nitric oxide synthase (NOS). Three isoforms of this enzyme encoded by distinct genes are known. 1,2 The constitutive isoforms are neuronal NOS (type I) and endothelial NOS (type III). Neuronal NOS is involved in neurotransmission, whereas NO derived from endothelial NOS has antithrombotic and vasorelaxing properties. Inducible NOS (type II, iNOS) is not expressed under normal conditions, but is induced by cytokines and endotoxin (lipopolysaccharide [LPS]) in various cell types including hepatocytes, macrophages, smooth muscle cells, and chondrocytes. 3 iNOS-derived NO is an important component of the nonspecific host defense against invading microbial agents. 4 It has been shown that mice lacking a functional iNOS gene are more susceptible to infection with Staphylococcus aureus 5 and Leishmania major. 6 Furthermore, inhibition of viral replication by NO is shown by many laboratories by using NO donors, inhibiting NO production by NOS-inhibitors, or by using iNOS knockout mice. 7 To induce iNOS messenger RNA (mRNA), activation of the transcription factor nuclear factor-B (NF-B) is essential 8-12 although probably not sufficient 13,14 for full iNOS induction. To induce gene transcription, NF-B must be translocated from the cytoplasm to the nucleus. 15 Nuclear translocation of NF-B is triggered by changes in the redox state. [16][17][18] Therefore, the intracellular glutathione (GSH) status may be a key determinant for the capacity of cells to express iNOS. Indeed, it has been shown that GSH depletion prevents iNOS induction and/or NO production in response to cytokines in cultured rat hepatocytes, 19,20 in the J774 macrophage cell line, 21 and in cultured macrophages. 22 To our knowledge, neither the relevance of the intracellular GSH status for the induction of iNOS in the liver in vivo nor the contribution of NF-B in the GSH-dependent iNOS expression has been reported.The aim of this study was to investigate the importance of the intracellular GSH status for the capacity of hepatocytes and inflammatory cells to express iNOS in response to endotoxin and/or cytokines in vivo and in vitro. MATERIALS AND METHODS Animals and Experimental Design in Vivo.Specified pathogen-free male Wistar rats (200-250 g) were purchased from Harlan-CPB, Zeist, the Netherlands. They were kept under routine laboratory

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“…We found that the LPS-inducible transactivation of the iNOS gene was significantly suppressed by 2Ј,8Љ-biapigenin. Because the promoter regions of both the iNOS and COX-2 genes contain NF-kB binding sites 17,19) and NF-kB is a key transcription factor for the regulation of both gene expressions, 20,21) we examined whether 2Ј,8Љ-biapigenin suppressed NF-kB activity. The reporter gene assay using NF-kB minimal promoter and nuclear p65 immunochemical detection clearly showed that 2Ј,8Љ-biapigenin significantly blocked the process of NF-kB activation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Nuclear Factor-.KAPPA.B Activation by 2',8"-Biapigenin

Woo

Pokharel

Yang

et al. 2006

Biological & Pharmaceutical Bulletin

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Chemoprevention is considered to be one of the most promising strategies for the prevention of human cancers. It is defined as the use of either natural or synthetic compounds to block or retard the carcinogenic process, and many natural candidates including epigallocatechin, genistein and sulforaphane have been evaluated in terms of malignancy prevention. 1-3)Recently, it was suggested that chronic inflammation is associated with carcinogenesis. 4,5) Chronic inflammation leads to the induction of specific enzymes in affected tissues and cells. In particular, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) are responsible for the exaggerated production of NO and prostaglandins, respectively, and are believed to be involved in the pathogenesis of cancer.6,7) COX-2 expression increases during tumor progression in the stomach, suggesting that COX-2 participates in gastric tumorigenesis.8) It has also been reported that there is a strong positive relationship between the presence of iNOS and the frequency of mutation in colon tumor tissues. 9)Hence, the overproduction of prostaglandins and NO may act as both an endogenous initiator and as a promoter of carcinogenesis and specific inhibitors of COX-2 or iNOS might have applications as chemopreventive agents in human cancer. Lee et al. 10) reported that the water-extracted fraction of Selaginella tamariscina (Selaginellaceae) efficiently increased p53 gene expression and induced G1 arrest, suggesting that S. tamariscina is a candidate chemopreventive. Crude extracts of S. tamariscina also reduced the production of proinflammatory cytokines, interleukin-1b, and tumor necrosis factor-a in human mesangial cells.11) As a part of our program to screen for potential cancer chemopreventive compounds from medicinal plants, we isolated 2Ј,8Љ-biapigenin from S. tamariscina (Fig. 1). The biological activity of 2Ј,8Љ-biapigenin has not been studied.In the present study, we investigated the modulating effects of the bi-flavonoid, 2Ј,8Љ-biapigenin on the expressions and activities of iNOS and COX-2 induced by lipopolysaccharide (LPS) in Raw264.7 macrophage cells. We found that 2Ј,8Љ-biapigenin inhibited nuclear factor (NF)-kB activation, and that this action is required for its blocking effects on iNOS and COX-2. MATERIALS AND METHODS Extraction and Isolation of 2,8؆-Biapigenin WholeSelaginella tamariscina (600 g) was extracted with MeOH at room temperature to afford 50.5 g of residue. The methanol extract was suspended in water and then sequentially partitioned in dichloromethane, ethyl acetate, and n-butanol. Three grams of the EtOAc fraction was subjected to silica gel column chromatography using a CHCl 3 -MeOH-H 2 O (12 : 1 : 0.1→8 : 1 : 0.1→5 : 1 : 0.1→2 : 1 : 0.1→1 : 1 : 0.1→Me OH only) gradient elution system. Fractions were combined based on their TLC patterns to yield subfractions designated as E1-E10. Subfraction E4 (438.9 mg) was purified by Sephadex LH 20 column chromatography using MeOH : H 2 Oϭ2 : 1 as eluant to give four subfractions (E41-E44). ...

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Evidence for Common Mechanisms in the Transcriptional Control of Type II Nitric Oxide Synthase in Isolated Hepatocytes

Abstract: Incubation of primary cultures of rat hepatocytes with lipopolysaccharide (LPS), S-[2,3-bis(palmitoyloxy)-(2-R,S)-propyl]-N-palmitoyl-(R)-

Cited by 90 publications

References 52 publications

4-Hydroxykobusin Inhibits the Induction of Nitric Oxide Synthase by Inhibiting NF-.KAPPA.B and AP-1 Activation

4-Hydroxykobusin Inhibits the Induction of Nitric Oxide Synthase by Inhibiting NF-.KAPPA.B and AP-1 Activation

Expression of inducible nitric oxide synthase in endotoxemic rat hepatocytes is dependent on the cellular glutathione status

Inhibition of Nuclear Factor-.KAPPA.B Activation by 2',8"-Biapigenin

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