In vivo Footprinting of the Mouse Inducible Nitric Oxide Synthase Gene: Inducible Protein Occupation of Numerous Sites Including Oct and NF-IL6

Goldring, Christopher E.; Reveneau, Sylvie; Algarté, Michèle; Jeannin, Jean–François

doi:10.1093/nar/24.9.1682

Cited by 88 publications

(69 citation statements)

References 34 publications

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“…These results suggest that C 2 -ceramide inhibition of LPSdependent signaling cascades leading to iNOS gene induction is dependent on the types of macrophages. Actually it is known that the iNOS gene is regulated by several coordinated transcription factors (63,64) and is distinctly induced in different cell types. For example, priming factors, such as IFN-␥, IL-1, TNF-␣, and Ca 2ϩ , are required for the maximal induction of iNOS expression in peritoneal macrophages (33,34,65) and C 6 -glioma cells (66).…”

Section: Discussionmentioning

confidence: 99%

Ceramide Inhibits Lipopolysaccharide-Mediated Nitric Oxide Synthase and Cyclooxygenase-2 Induction in Macrophages: Effects on Protein Kinases and Transcription Factors

Hsu

Chi

Huang

et al. 2001

The Journal of Immunology

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The goal of this study was to elucidate whether triggering the sphingomyelin pathway modulates LPS-initiated responses. For this purpose we investigated the effects of N-acetylsphingosine (C2-ceramide) on LPS-induced production of NO and PGE2 in murine RAW 264.7 macrophages and explored the signaling pathways involved. We found that within a range of 10–50 μM, C2-ceramide inhibited LPS-elicited NO synthase and cyclooxygenase-2 induction accompanied by a reduction in NO and PGE2 formation. By contrast, a structural analog of C2-ceramide that does not elicit functional activity, C2-dihydroceramide, did not affect the LPS response. The nuclear translocation and DNA binding study revealed that ceramide can inhibit LPS-induced NF-κB and AP-1 activation. The immunocomplex kinase assay indicated that IκB kinase activity stimulated by LPS was inhibited by ceramide, which concomitantly reduced the IκBα degradation caused by LPS within 1–6 h. In concert with the decreased cytosolic p65 protein level, LPS treatment resulted in rapid nuclear accumulation of NF-κB subunit p65 and its association with the cAMP-responsive element binding protein. Ceramide coaddition inhibited all the LPS responses. In addition, LPS-induced PKC and p38 mitogen-activated protein kinase activation were overcome by ceramide. In conclusion, we suggest that ceramide inhibition of LPS-mediated induction of inducible NO synthase and cyclooxygenase-2 is due to reduction of the activation of NF-κB and AP-1, which might result from ceramide’s inhibition of LPS-stimulated IκB kinase, p38 mitogen-activated protein kinase, and protein kinase C.

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Section: Discussionmentioning

confidence: 99%

Ceramide Inhibits Lipopolysaccharide-Mediated Nitric Oxide Synthase and Cyclooxygenase-2 Induction in Macrophages: Effects on Protein Kinases and Transcription Factors

Hsu

Chi

Huang

et al. 2001

The Journal of Immunology

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“…The murine iNOS promoter contains 12 nucleotide sequences that conform to the consensus C/EBP␤ box TKNNGYAAK (43). Using footprinting analysis of the 5Ј-flanking region of the iNOS gene in activated RAW 264.7 cells, Goldring et al (41) have also demonstrated protection of guanine 146 within the C/EBP␤ box, suggesting that C/EBP␤ binds to this site. In addition, correlative changes in the activation of C/EBP␤ and the expression of the iNOS gene in cultured cardiac myocytes and vascular smooth muscle cells (40,42) provided evidence to suggest a role for C/EBP␤ in the expression of iNOS.…”

Section: Cd40 Ligation Stimulates the Production Of No In Ifn-␥-treatmentioning

confidence: 99%

Ligation of CD40 Stimulates the Induction of Nitric-oxide Synthase in Microglial Cells

Jana¹,

Liu²,

Koka³

et al. 2001

Journal of Biological Chemistry

108

138

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Nitric oxide (NO), a diffusible gas, plays an important role in many physiological and diverse pathophysiological conditions (1, 2). At low concentrations NO has been shown to play a unique role in neurotransmission and vasodilation, whereas at higher concentrations it is neurotoxic (1, 2). Consistently, NO, which is derived in excessive amounts from the activation of inducible nitric-oxide synthase (iNOS) 1 in glial cells (microglia and astrocytes), is assumed to contribute to oligodendrocyte degeneration in demyelinating diseases and neuronal death during neurodegenerative diseases (3-7). Evidence from several laboratories emphasizes the involvement of NO in the pathophysiology of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), the animal model of MS (4, 8, 9). Analysis of cerebrospinal fluid from MS patients has shown increased levels of nitrite and nitrate compared with normal controls (11). The reaction of NO with O 2 Ϫ forms peroxynitrite (ONOO Ϫ ), a strong nitrosating agent capable of nitrosating tyrosine residues of a protein to nitrotyrosine. Increased levels of nitrotyrosine have been found in demyelinating lesions of MS brains as well as in spinal cords of mice with EAE (12, 13). Subsequently, a semiquantitative reverse transcription-PCR for iNOS mRNA in MS brains also shows a markedly higher expression of iNOS mRNA in MS brains than in normal brains (6,14).CD40, a 45-50-kDa receptor, is a member of the tumor necrosis factor (TNF) receptor superfamily and is expressed in a wide range of both immune and non-immune cell types (16 -18). Recently, several investigators have shown that enhanced CD40-CD40 ligation can be dangerous to the host as it is involved in the pathogenesis of a number of autoimmune inflammatory diseases (e.g. MS, arthritis, insulin-dependent diabetes) (19 -21). High levels of CD40 ligand (CD40L)-expressing cells co-localize with CD40-positive cells in both MS and EAE; most of these CD40-positive cells are of the monocytic lineage (macrophages or microglia) (19,20). Furthermore, the importance of CD40-CD40L interaction in the disease process of EAE/MS has been highlighted by the fact that administration of anti-CD40L monoclonal antibody attenuates the development of EAE (20,21) and that EAE cannot be induced in CD40L(Ϫ/Ϫ) mice (19). However, the molecular events surrounding the marked increase of CD40 ligation in neural tissues of MS patients and EAE animals are not completely understood.

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“…iNOS is one of several TNF-regulated genes that are known to protect hepatocytes from LPS toxicity (50 -52). Moreover, LPS-mediated transcriptional activation of the murine iNOS gene requires TNF-initiated signals that enhance NF-B activity (53)(54)(55). LPS increases iNOS mRNA levels similarly in ethanol-and pair-fed mice (Fig.…”

Section: Induction Of Nf-b and Inos An Nf-b Targetmentioning

confidence: 99%

Chronic Ethanol Exposure Potentiates Lipopolysaccharide Liver Injury Despite Inhibiting Jun N-terminal Kinase and Caspase 3 Activation

Koteish

Yang

Lin

et al. 2002

Journal of Biological Chemistry

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Although ethanol is known to sensitize hepatocytes to tumor necrosis factor (TNF) lethality, the mechanisms involved remain controversial. Recently, others have shown that adding TNF␣ to cultures of ethanol-pretreated hepatocytes provokes the mitochondrial permeability transition, cytochrome c release, procaspase 3 activation, and apoptosis. Although this demonstrates that ethanol can sensitize hepatocytes to TNF-mediated apoptosis, the hepatic inflammation and ballooning hepatocyte degeneration that typify alcohol-induced liver injury suggest that other mechanisms might predominate in vivo. To evaluate this possibility, acute responses to lipopolysaccharide (LPS), a potent inducer of TNF␣, were compared in mice that had been fed either an ethanol-containing or control diet for 5 weeks. Despite enhanced induction of cytokines such as interleukin (IL)-10, IL-15, and IL-6 that protect hepatocytes from apoptosis, ethanol-fed mice exhibited a 4 -5-fold increase in serum alanine aminotransferase after LPS, confirming increased liver injury. Six h post-LPS histology also differed notably in the two groups, with control livers demonstrating only scattered apoptotic hepatocytes, whereas ethanol-exposed livers had large foci of ballooned hepatocytes, inflammation, and scattered hemorrhage. No caspase 3 activity was noted during the initial 6 h after LPS in ethanol-fed mice, but this tripled by 1.5 h after LPS in controls. Procaspase 8 cleavage and activity of the apoptosis-associated kinase, Jun N-terminal kinase, were also greater in controls. In contrast, ethanol exposure did not inhibit activation of cytoprotective mitogen-activated protein kinases and AKT or attenuate induction of the anti-apoptotic factors NF-B and inducible nitric oxide synthase. Consistent with these responses, neither cytochrome c release, an early apoptotic response, nor hepatic oligonucleosomal DNA fragmentation, the ultimate consequence of apoptosis, was increased by ethanol. Thus, ethanol exacerbates TNF-related hepatotoxicity in vivo without enhancing caspase 3-dependent apoptosis.

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In vivo Footprinting of the Mouse Inducible Nitric Oxide Synthase Gene: Inducible Protein Occupation of Numerous Sites Including Oct and NF-IL6

Cited by 88 publications

References 34 publications

Ceramide Inhibits Lipopolysaccharide-Mediated Nitric Oxide Synthase and Cyclooxygenase-2 Induction in Macrophages: Effects on Protein Kinases and Transcription Factors

Ceramide Inhibits Lipopolysaccharide-Mediated Nitric Oxide Synthase and Cyclooxygenase-2 Induction in Macrophages: Effects on Protein Kinases and Transcription Factors

Ligation of CD40 Stimulates the Induction of Nitric-oxide Synthase in Microglial Cells

Chronic Ethanol Exposure Potentiates Lipopolysaccharide Liver Injury Despite Inhibiting Jun N-terminal Kinase and Caspase 3 Activation

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