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LPS-induced iNOS expression in Bv-2 cells is suppressed by an oxidative mechanism acting on the JNK pathway-A potential role for neuroprotection
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry.
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2010 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1322, no March 2010, 1-7 p.Article in journal (Refereed) Published
Abstract [en]

Activated microglia cells, observed during chronic inflammation, produce and secrete compounds that at high concentrations or during sustained production might cause neuronal cell death. Inducible nitric oxide synthase (iNOS) is expressed in response to various immunological stimuli and catalyses the formation of the free radical nitric oxide (NO), that at low and regulated levels participate in cell signaling and cytoprotective events, whereas its higher and unregulated production can promote neurotoxicity in cells or in tissues. Regulation of NO production is therefore central for maintaining NO-levels within a safe window. We have analyzed iNOS protein expression and NO production, in murine microglial Bv-2 cells after 16 h treatment with the bacterial endotoxin lipopolysaccharide (LPS). We have further analyzed three MAPK pathways, by co-treating the cells with LPS and the inhibitors of ERK1/2, p38 or JNK MAPK activities. To investigate participation of an oxidative regulatory mechanism, cells were also treated with the antioxidant N-acetyl-L-cysteine (NAC). Our results show that LPS-induced iNOS expression in Bv-2 cells is mainly mediated through JNK MAPK. In addition, co-treatment of the Bv-2 cells with LPS and NAC surprisingly further increased the iNOS expression, an effect also found to be mediated through the JNK MAPK pathway. The level of phosphorylated JNK MAPK (p46) was strongly increased by LPS alone and was further increased when combined with NAC. Our data indicate that iNOS and NO production are suppressed by an oxidative mechanism acting on the JNK MAPK pathway and we speculate that it might constitute a potential regulatory mechanism controlling the NO level.

Place, publisher, year, edition, pages
2010. Vol. 1322, no March 2010, 1-7 p.
Keyword [en]
Microglial activation, Inflammation, Signal transduction pathways, NAC, ROS (Reactive oxygen species)
National Category
Neurosciences
Research subject
Neurochemistry and Neurotoxicology
Identifiers
URN: urn:nbn:se:su:diva-50134DOI: 10.1016/j.brainres.2010.01.082ISI: 000276621800001OAI: oai:DiVA.org:su-50134DiVA: diva2:380582
Note
authorCount :5Available from: 2010-12-21 Created: 2010-12-21 Last updated: 2011-05-05Bibliographically approved
In thesis
1. Altered cell signaling linked to neurodegeneration: Studies on scrapie-infected neuroblastoma cells and activated microglia 
Open this publication in new window or tab >>Altered cell signaling linked to neurodegeneration: Studies on scrapie-infected neuroblastoma cells and activated microglia 
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prion diseases are neurodegenerative disorders that can affect humans and animals. The underlying event is a conformational change of the normal cellular prion protein (PrPC) into an aberrant isoform termed PrP-scrapie (PrPSc). PrPSc is thought to lead to neurodegeneration and activation of glial cells.

Scrapie infection of neuroblastoma cells was shown to increase the expression of insulin receptor (IR). Additionally, a marked reduction of 125I-insulin binding sites was observed. Insulin stimulation showed alteration in both IR β-subunit tyrosine phosphorylation and extracellular signal regulated kinase-2 (ERK2) activity.  Furthermore, scrapie infection was shown to increase insulin-like growth factor-1(IGF-1) receptor (IGF-1R) expression, although the number of 125I-IGF-1-binding sites was reduced. Also binding affinity of 125I-IGF-1 to its receptor was reduced, and tyrosine phosphorylation of IGF-1R-β-subunit in response to IGF-1 was altered. The increased levels of neurotrophic receptors might represent a neuroprotective response to prion infection. However, scrapie infection instead leads to decreased function, decreased levels of functional receptors, or both, which could promote neurodegeneration in prion diseases, through attenuated neurotrophic support.

In BV-2 microglial cells, LPS-induced iNOS (inducible nitric oxide synthase) expression and subsequent NO production were mainly mediated through c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway. Antioxidant treatment indicates that oxidative suppressing mechanism(s) acts on JNK pathway possibly as a regulatory mechanism controlling the NO levels. The JNK pathway was also shown to play an important role in the survival of BV-2 cells. We show that BV-2 cells are protected from ongoing apoptosis by pro-survival activity mediated both by the JNK and p38 MAPK pathway during LPS-induced inflammation. This is very interesting findings since it is important for microglia to respond properly to a pathogen, without themselves being affected and undergo apoptosis.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2011. 58 p.
Keyword
Prion disease, Inflammation, MAPK, Microglia activation, Neuroblastoma
National Category
Neurosciences
Research subject
Neurochemistry and Neurotoxicology
Identifiers
urn:nbn:se:su:diva-57222 (URN)978-91-7447-285-1 (ISBN)
Public defence
2011-06-09, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 13:00 (English)
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Available from: 2011-05-12 Created: 2011-05-04 Last updated: 2011-05-26Bibliographically approved

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