| NFκB activation and stimulation of chemokine production in normal human macrophages by the gadolinium-based magnetic resonance contrast agent Omniscan: possible role in the pathogenesis of nephrogenic systemic fibrosis. | |
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MedLine Citation:
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PMID: 20959327 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is a generalised fibrotic disorder occurring in certain individuals with renal insufficiency exposed to gadolinium-based contrast agents (GdBCA) for MRI. Histopathological examination of affected tissues shows increased numbers of activated macrophages. To elucidate the mechanisms responsible for macrophage activation, the effects of the GdBCA Omniscan on normal human macrophage global gene expression, chemokine production and nuclear factor κB (NFκB) activation was examined. METHODS: Normal human monocyte-derived macrophages were incubated with Omniscan (50 mM) and their gene expression analysed by microarrays and real-time PCR. Macrophage chemokine production was assayed by multiplex ELISA. NFκB activation was assessed by NFκB nuclear localisation and quantitation of intracellular levels of inducible nitric oxide synthase (iNOS) protein. A specific cell-permeable NFκB peptide inhibitor was used to abrogate NFκB stimulation of chemokine and iNOS protein levels. CCL8/MCP-2 in affected skin of patients with NSF was examined by indirect immunofluorescence. RESULTS: Omniscan caused a profound change in the transcriptome of differentiated human normal macrophages in vitro, including a large increase in the expression of genes encoding CC and CXC chemokines. It induced rapid nuclear localisation of NFκB and stimulation of iNOS protein levels and chemokine production which were blocked by an NFκB inhibitory peptide. CCL8/MCP-2, the most upregulated chemokine following in vitro macrophage exposure to Omniscan, was strongly increased in NSF-affected skin. CONCLUSION: The GdBCA Omniscan induces potent stimulation of macrophage gene expression, NFκB activation and increased NFκB-mediated production of CC and CXC chemokines and iNOS. These alterations may play a crucial role in the pathogenesis of NSF. |
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Authors:
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Francesco Del Galdo; Peter J Wermuth; Sankar Addya; Paolo Fortina; Sergio A Jimenez |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Annals of the rheumatic diseases Volume: 69 ISSN: 1468-2060 ISO Abbreviation: Ann. Rheum. Dis. Publication Date: 2010 Nov |
Date Detail:
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Created Date: 2010-10-20 Completed Date: 2010-11-12 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372355 Medline TA: Ann Rheum Dis Country: England |
Other Details:
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Languages: eng Pagination: 2024-33 Citation Subset: IM |
Affiliation:
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Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Cell Differentiation Cell Nucleus / metabolism Cells, Cultured Chemokine CCL8 / metabolism Chemokines / biosynthesis* Contrast Media / pharmacology* Gadolinium DTPA / pharmacology* Gene Expression Regulation / drug effects Humans Macrophages / drug effects*, metabolism, pathology NF-kappa B / metabolism* Nephrogenic Fibrosing Dermopathy / chemically induced*, metabolism Nitric Oxide Synthase Type II / metabolism Polymerase Chain Reaction / methods Signal Transduction / physiology Skin / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 AR-019616/AR/NIAMS NIH HHS; T32 AR-007583/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/CCL8 protein, human; 0/Chemokine CCL8; 0/Chemokines; 0/Contrast Media; 0/NF-kappa B; 122795-43-1/gadodiamide; 80529-93-7/Gadolinium DTPA; EC 1.14.13.39/Nitric Oxide Synthase Type II |
| Comments/Corrections | |
Comment In:
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Ann Rheum Dis. 2010 Nov;69(11):1895-7
[PMID:
20959325
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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