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Expression of inducible nitric oxide synthase by neurones following exposure to endotoxin and cytokine.

ABSTRACT: In the CNS, nitric oxide (NO) has been implicated as both a mediator of neurotoxicity and a neuromodulator. The inducible NO synthase (iNOS), thought to mediate toxic effects of NO, has been attributed to glial cells in the CNS. We now report that cerebellar granule cell neurones can be stimulated by lipopolysaccharide and interferon-gamma to express iNOS in vitro, as demonstrated by reverse transcription-polymerase chain reaction and fluorescent in situ hybridisation. The expression of both constitutive NO synthase (cNOS) and iNOS by neurones suggests that NO has diverse functions in the brain, and supports the possibility that iNOS plays a role in neuronal damage and inflammation following activation of brain microglia and production of cytokines.

SUBMITTER: Minc-Golomb D

PROVIDER: S-EPMC1910215 | biostudies-other | 1994 Jul

REPOSITORIES: biostudies-other

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Expression of inducible nitric oxide synthase by neurones following exposure to endotoxin and cytokine.

Minc-Golomb D D Tsarfaty I I Schwartz J P JP

British journal of pharmacology 19940701 3

In the CNS, nitric oxide (NO) has been implicated as both a mediator of neurotoxicity and a neuromodulator. The inducible NO synthase (iNOS), thought to mediate toxic effects of NO, has been attributed to glial cells in the CNS. We now report that cerebellar granule cell neurones can be stimulated by lipopolysaccharide and interferon-gamma to express iNOS in vitro, as demonstrated by reverse transcription-polymerase chain reaction and fluorescent in situ hybridisation. The expression of both con ...[more]

PMID: 7522856

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Project description:Inducible nitric oxide synthase (iNOS) activity increases in acute and chronic inflammatory lung diseases. Imaging iNOS expression may be useful as an inflammation biomarker for monitoring lung disease activity. We developed a novel tracer for PET that binds to iNOS in vivo, (18)F-NOS. In this study, we tested whether (18)F-NOS could quantify iNOS expression from endotoxin-induced lung inflammation in healthy volunteers.Healthy volunteers were screened to exclude cardiopulmonary disease. Qualifying volunteers underwent a baseline, 1-h dynamic (18)F-NOS PET/CT scan. Endotoxin (4 ng/kg) was then instilled bronchoscopically in the right middle lobe. (18)F-NOS imaging was performed again approximately 16 h after endotoxin instillation. Radiolabeled metabolites were determined from blood samples. Cells recovered by bronchoalveolar lavage (BAL) after imaging were stained immunohistochemically for iNOS. (18)F-NOS uptake was quantified as the distribution volume ratio (DVR) determined by Logan plot graphical analysis in volumes of interest placed over the area of endotoxin instillation and in an equivalent lung region on the left. The mean Hounsfield units (HUs) were also computed using the same volumes of interest to measure density changes.Seven healthy volunteers with normal pulmonary function completed the study with evaluable data. The DVR increased by approximately 30%, from a baseline mean of 0.42 ± 0.07 to 0.54 ± 0.12, and the mean HUs by 11% after endotoxin in 6 volunteers who had positive iNOS staining in BAL cells. The DVR did not change in the left lung after endotoxin. In 1 volunteer with low-level iNOS staining in BAL cells, the mean HUs increased by 7% without an increase in DVR. Metabolism was rapid, with approximately 50% of the parent compound at 5 min and 17% at 60 min after injection.(18)F-NOS can be used to image iNOS activity in acute lung inflammation in humans and may be a useful PET tracer for imaging iNOS expression in inflammatory lung disease.

Project description:In rheumatoid arthritis (RA), nitric oxide (NO) is implicated in inflammation, angiogenesis and tissue destruction. The enzyme inducible nitric oxide synthase (iNOS) is responsible for the localised over-production of NO in the synovial joints affected by RA. The pro- and anti-inflammatory cytokines stimulate the synovial macrophages and the fibroblast-like synoviocytes to express iNOS. Therefore, the cytokine signalling network underlying the regulation of iNOS is essential to understand the pathophysiology of the disease. By using information from the literature, we have constructed, for the first time, the cytokine signalling network involved in the regulation of iNOS expression. Using the differential expression patterns obtained by re-analysing the microarray data on the RA synovium and the synovial macrophages available in the Gene Expression Omnibus (GEO) database, we aimed to establish the role played by the network genes towards iNOS regulation in the RA synovium. Our analysis reveals that the network genes belonging to interferon (IFN) and interleukin-10 (IL-10) pathways are always up-regulated in the RA synovium whereas the genes which are part of the anti-inflammatory transforming growth factor-beta (TGF-?) signalling pathway are mostly down-regulated. We observed a consistent up-regulation of the transcription factor signal transducers and activators of transcription 1 (STAT1) in the RA synovium and the macrophages. Interestingly, we found a consistent up-regulation of the iNOS interacting protein ras-related C3 botulinum toxin substrate 2 (RAC2) in the RA synovium as well as the macrophages. Importantly, we have constructed a model to explain the impact of IFN and IL-10 pathways on Rac2-iNOS interaction leading to over-production of NO and thereby causing chronic inflammation in the RA synovium. The interplay between STAT1 and RAC2 in the regulation of NO could have implications for the identification of therapeutic targets for RA.

Dataset Information

Expression of inducible nitric oxide synthase by neurones following exposure to endotoxin and cytokine.

Publications

Expression of inducible nitric oxide synthase by neurones following exposure to endotoxin and cytokine.

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