In Murine 3T3 Fibroblasts, Different Second Messenger Pathways Resulting in the Induction of NO Synthase II (iNOS) Converge in the Activation of Transcription Factor NF-κB

Kleinert, Hartmut; Euchenhofer, Christian; Ihrig-Biedert, Irmgard; Förstermann, Ulrich

doi:10.1074/jbc.271.11.6039

Cited by 122 publications

(84 citation statements)

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“…In this study, we have demonstrated that NF-B inhibitors abrogate SDF1␣-induced chemotactic effects. NOrelated compounds have been shown to activate NF-B activity (42). Moreover, the transcriptional activity of NF-B has been shown to regulate iNOS gene expression (68,69).…”

Section: Discussionmentioning

confidence: 99%

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Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

Cherla

Ganju

2001

The Journal of Immunology

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Stromal cell-derived factor 1α (SDF1α) and its cognate chemokine receptor CXCR4 act as potent chemoattractants and regulate trafficking and homing of hematopoietic progenitor cells and lymphocytes. However, the molecular mechanisms regulating SDF1α-driven cell migration are not well defined. In this study, we have explored the roles of the second messenger NO and the transcription factor NF-κB in SDF1α-induced T cell migration. SDF1α treatment of Jurkat T cells increased the activity of NO synthase, which catalyzes the generation of NO. We observed that pretreatment of Jurkat cells or activated PBLs with several NO donors significantly enhanced the SDF1α-induced migration, whereas various inhibitors of NO synthase markedly abrogated the chemotactic response in a concentration-dependent manner. Furthermore, we observed that inhibitors of the transcription factor NF-κB, which is linked to NO signaling pathways, also significantly blocked the SDF1α-induced chemotactic response. However, these compounds did not have a significant effect on SDF1α-induced mitogen-activated protein kinase activity. In addition, the MAP/Erk kinase kinase inhibitor PD98059 did not abrogate SDF1α-induced chemotaxis. AKT, which has been shown to mediate NO production, was also phosphorylated upon SDF1α stimulation. These studies suggest that NO-related signaling pathways may mediate SDF1α-induced chemotaxis, but not mitogen-activated protein kinase activation.

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Section: Discussionmentioning

confidence: 99%

“…NF-B has been shown to influence NO production by regulating expression of the inducible NO synthase gene (42). Conversely, NO has also been shown to be capable of modulating NF-B function in mononuclear leukocytes and endothelial cells (43,44).…”

mentioning

confidence: 99%

Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

Cherla

Ganju

2001

The Journal of Immunology

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“…Such as, cAMP induces the expression of iNOS in LPS-and cytokine-stimulated glomerular mesangial cells (Muhl et al, 1994), vascular smooth muscle cells (Koide et al, 1993), cardiac myocytes (Ikeda et al, 1996), murine 3T3 fibroblasts (Kleinert et al, 1996) and rat peritoneal macrophages (Sowa and Przewlocki, 1994). In these studies, the increase in cAMP level resulting due to inhibition of phosphodiesterase (an enzyme that degrades cAMP), or due to an exogenous input of cAMP derivatives or compounds that enhance intracellular levels of cAMP, induce and/or stimulate iNOS expression.…”

Section: The Camp In Glial Inos Regulation: Unique Regulation By Campmentioning

confidence: 99%

Signals for the induction of nitric oxide synthase in astrocytes

Saha

Pahan

2006

Neurochemistry International

104

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Nitric oxide (NO), being a double-edged sword depending on its concentration in the microenvironment, is involved in both physiological and pathological processes of many organ systems including brain and spinal cord. It is now well-documented that once inducible nitric oxide synthase (iNOS) is expressed in CNS in a signal-dependent fashion, NO in excess of physiological thresholds is produced and this excess NO then plays a role in the pathogenesis of stroke, demyelination and other neurodegenerative diseases. Therefore, a keen interest has been generated in recent years in comprehending the regulation of this enzyme in brain cells. The present review summarizes our current understanding of signaling mechanisms leading to transcription of the iNOS gene in activated astrocytes. We attempt this comprehension with a hope to identify potential targets to intervene NO-mediated CNS disorders.

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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.…”

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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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In Murine 3T3 Fibroblasts, Different Second Messenger Pathways Resulting in the Induction of NO Synthase II (iNOS) Converge in the Activation of Transcription Factor NF-κB

Cited by 122 publications

References 56 publications

Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

Signals for the induction of nitric oxide synthase in astrocytes

Expression of Inducible Nitric Oxide Synthase in Endotoxemic Rat Hepatocytes Is Dependent on the Cellular Glutathione Status

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