Nuclear factor <i>κ</i>B is required for the transcriptional control of type II NO synthase in regenerating liver

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

doi:10.1042/bj3260791

Cited by 45 publications

(50 citation statements)

References 43 publications

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“…Endothelial NOS can also be activated by phosphorylation via the phosphatidylinositol 3-kinase (PI-3K)/Akt pathway in response to shear stress in endothelial cells (51,52), and this pathway may also exist in macrophages. LPS has been shown to increase the activity of PI-3K in RAW 264.7 murine macrophages (53), and vascular endothelial growth factor can stimulate intercellular adhesion molecule 1 expression via a PI-3K/Akt/NO-dependent process in brain microvascular endothelial cells (54). Because intercellular adhesion molecule 1 is up-regulated by NF-B, this represents evidence that NO from phosphorylation-activated eNOS might activate this transcription factor.…”

Section: Discussionmentioning

confidence: 77%

Macrophage Endothelial Nitric-oxide Synthase Autoregulates Cellular Activation and Pro-inflammatory Protein Expression

Connelly¹,

Jacobs²,

Palacios-Callender

et al. 2003

Journal of Biological Chemistry

162

114

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Expression of inducible nitric-oxide (NO) synthase (iNOS) and "high-output" production of NO by macrophages mediates many cytotoxic actions of these immune cells. However, macrophages have also been shown to express a constitutive NOS isoform, the function of which remains obscure. Herein, bone marrowderived macrophages (BMDMØs) from wild-type and endothelial NOS (eNOS) knock-out (KO) mice have been used to assess the role of this constitutive NOS isoform in the regulation of macrophage activation. BMDMØs from eNOS KO animals exhibited reduced nuclear factor-B activity, iNOS expression, and NO production after exposure to lipopolysaccharide (LPS) as compared with cells derived from wild-type mice. Soluble guanylate cyclase (sGC) was identified in BMDMØs at a mRNA and protein level, and activation of cells with LPS resulted in accumulation of cyclic GMP. Moreover, the novel non-NO-based sGC activator, BAY 41-2272, enhanced BMDMØ activation in response to LPS, and the sGC inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one attenuated activation. These observations provide the first demonstration of a pathophysiological role for macrophage eNOS in regulating cellular activation and suggest that NO derived from this constitutive NOS isoform, in part via activation of sGC, is likely to play a pivotal role in the initiation of an inflammatory response.Nitric oxide (NO) 1 production by the inducible isoform of NO synthase (iNOS) plays a pivotal role in numerous and diverse pathophysiological processes, particularly as a principal mediator of the microbicidal and tumoricidal actions of macrophages (1-3). Inducible NOS is expressed in many cell types in response to a wide range of inflammatory cytokines including interleukin-1␤, interleukin-2, interferon-␥, tumor necrosis factor-␣, and bacterial metabolites such as lipopolysaccharide (LPS) (4, 5). The inherent activity exhibited by iNOS results in the production of "high-output" NO, which is cytotoxic and cytostatic to a number of pathogens and tumor cells; this is mediated via inhibition of various enzymes within target cells including complexes I and IV of the mitochondrial respiratory chain (6 -9), ribonucleotide reductase (10), aconitase (3), and glyceraldehyde-6-phosphate dehydrogenase (11) and through DNA modification (12, 13).It is now becoming clear that NO plays a pivotal role in the regulation of gene expression (14 -18). One key facet of this regulatory activity may be the control of iNOS induction (19 -22). Such a mechanism would constitute a self-regulating pathway by which NO production from this NOS isoform could be fine tuned, which is essential because iNOS is regulated transcriptionally rather than biochemically. We have reported recently that NO has a patent biphasic effect on nuclear factor-B (NF-B) activity in murine macrophages and hence possesses the ability both to up-and down-regulate the expression of a number of pro-inflammatory proteins, including enzymes such as iNOS, cyclooxygenase-2, and interleukin-6 (17). The dual effect of NO on NF-B h...

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Section: Discussionmentioning

confidence: 77%

Macrophage Endothelial Nitric-oxide Synthase Autoregulates Cellular Activation and Pro-inflammatory Protein Expression

Connelly¹,

Jacobs²,

Palacios-Callender

et al. 2003

Journal of Biological Chemistry

162

114

View full text Add to dashboard Cite

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“…These reports provide information on signaling pathways for NOS-2 expression at 4 -6 or 20 -24 h but did not provide kinetic data. For example, Salh et al (25) report the inhibition of NOS-2 expression at 6 h by LY294002, whereas Diaz-Guerra et al (26) and Chen et al (27) report the involvement of PKC in NOS-2 expression at 24 h. Diaz-Guerra et al (28) report that NO production stimulated by LPSϩIFN-␥ for 24 h was augmented by LY294002. These results are consistent with our findings that PI3K mediates NOS-2 expression at 4 -6 h and negatively regulates its expression at 24 h. Taken together, these results support the notion that NOS-2 expression stimulated by LPSϩIFN-␥ comprises two distinct phases that are signaled by different pathways: 1) an early phase of expression, which is signaled through PI3K, p38 MAPK, and Jak 2/3; and 2) a late phase of expression, which is signaled via PKC and mammalian target of rapamycin.…”

Section: Nos-2 and Cox-2 Expression At 4 H Was Mediated By A Similarmentioning

confidence: 98%

Salicylate Suppresses Macrophage Nitric-oxide Synthase-2 and Cyclo-oxygenase-2 Expression by Inhibiting CCAAT/Enhancer-binding Protein-β Binding via a Common Signaling Pathway

Cieslik

Zhu

2002

Journal of Biological Chemistry

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We determined whether salicylate at pharmacological concentrations inhibits nitric-oxide synthase-2 (NOS-2) and cyclo-oxygenase-2 (COX-2) expressions in RAW 264.7 stimulated with lipopolysaccharide (LPS) and interferon-γ (IFN-γ). Cells were treated with sodium salicylate (10−7-10−4m) or vehicle for 30 min followed by LPS+IFN-γ for up to 24 h. Salicylate suppressed NOS-2 and COX-2 protein levels and promoter activities stimulated by LPS+IFN-γ for 4 h in a concentration-dependent manner but had no effect on NOS-2 expression stimulated by the combined agonists for 24 h. Results from promoter analysis indicate that the binding of CCAAT/enhancer-binding protein β (C/EBPβ) to its cognate site at −150/−142 on the NOS-2 promoter region was essential for NOS-2 expression at 4 h but not at 24 h. Salicylate reduced C/EBPβ binding at 4 h and did not alter its binding at 24 h. NOS-2 and COX-2 protein levels and C/EBPβ binding stimulated by LPS+IFN-γ for 4 h were inhibited by a similar battery of signaling inhibitors, suggesting a common pathway for NOS-2 and COX-2 expression. Kinetic analysis indicates that NOS-2, similar to COX-2 expression, at 4 h was largely due to the action of LPS, which induced C/EBPβ binding, whereas its expression at a longer time point was contributed by IFN-γ. Our findings implicate two distinct pathways for NOS-2 expression induced by LPS+IFN-γ. Salicylate at pharmacological concentrations is capable of suppressing the early phase of NOS-2 and COX-2 expression by blocking C/EBPβ binding.

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“…Cellular debris was removed by centrifugation for 2 min at 4°C, and the supernatant fraction was stored at Ϫ70°C. The gel mobility shift assay was performed essentially as previously described (32). The double-stranded oligonucleotide used as C/EBP␣ probe, corresponding to the nuclear factor-interleukin-6 (NF-IL6) site of the COX2 promoter (5Ј-GGGTATTATGCAATTG-GAAG-3Ј), was synthesized in a Pharmacia oligonucleotide synthesizer.…”

Section: Methodsmentioning

confidence: 99%

Insulin-induced Up-regulated Uncoupling Protein-1 Expression Is Mediated by Insulin Receptor Substrate 1 through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Fetal Brown Adipocytes

Valverde

Arribas

Mur

et al. 2003

Journal of Biological Chemistry

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Nuclear factor κB is required for the transcriptional control of type II NO synthase in regenerating liver

Cited by 45 publications

References 43 publications

Macrophage Endothelial Nitric-oxide Synthase Autoregulates Cellular Activation and Pro-inflammatory Protein Expression

Macrophage Endothelial Nitric-oxide Synthase Autoregulates Cellular Activation and Pro-inflammatory Protein Expression

Salicylate Suppresses Macrophage Nitric-oxide Synthase-2 and Cyclo-oxygenase-2 Expression by Inhibiting CCAAT/Enhancer-binding Protein-β Binding via a Common Signaling Pathway

Insulin-induced Up-regulated Uncoupling Protein-1 Expression Is Mediated by Insulin Receptor Substrate 1 through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Fetal Brown Adipocytes

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