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Interleukin-18 alters protein expressions of neurodegenerative diseases-linked proteins in human SH-SY5Y neuron-like cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
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2014 (English)In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 8, 214- p.Article in journal (Refereed) Published
Abstract [en]

Chronic inflammation and oxidative stress (OS) are present in Alzheimer's disease (AD) brains in addition to neuronal loss, Amyloid-beta (A beta) plaques and hyperphosphorylated tau-protein neurofibrillary tangles (NFTs). Previously we showed that levels of the pro-inflammatory cytokine, interleukin-18 (IL-18), are elevated in post-mortem AD brains. IL-18 can modulate the tau kinases, Cdk5 and GSK3?, as well as A beta-production. IL-18 levels are also increased in AD risk diseases, including type-2 diabetes and obesity. Here, we explored other IL-18 regulated proteins in neuron-like SH-SY5Y cells. Differentiated SH-SY5Y cells, incubated with IL-18 for 24, 48, or 72 h, were analyzed by two-dimensional gel electrophoresis (2D-DIGE). Specific altered protein spots were chosen and identified with mass spectrometry (MS) and verified by western immunoblotting (WIB). IL-18 had time-dependent effects on the SH-SY5Y proteome, modulating numerous protein levels/modifications. We concentrated on those related to OS (DDAH2, peroxiredoxins 2, 3, and 6, DJ-1, BLVRA), A beta-degradation (MMP14, TIMP2), A beta-aggregation (Septin-2), and modifications of axon growth and guidance associated, collapsin response mediator protein 2 (CRMP2). IL-18 significantly increased antioxidative enzymes, indicative of OS, and altered levels of glycolytic beta- and alpha-enolase and multifunctional 14-3-3 beta and -beta, commonly affected in neurodegenerative diseases. MMP14, TIMP2, alpha-enolase and 14-3-3 beta, indirectly involved in A? metabolism, as well as Septin-2 showed changes that increase A? levels. Increased 14-3-3 beta may contribute to GSK3 beta driven tau hyperphosphorylation and CRMP2 Thr514 and Ser522 phosphorylation with the Thr555-site, a target for Rho kinase, showing time-dependent changes. IL-18 also increased caspase-1 levels and vacuolization of the cells. Although our SH-SY5Y cells were not aged, as neurons in AD, our work suggests that heightened or prolonged IL-18 levels can drive protein changes of known relevance to AD pathogenesis.

Place, publisher, year, edition, pages
2014. Vol. 8, 214- p.
Keyword [en]
Interleukin-18, inflammation, neurodegenerative diseases, proteomics, oxidative stress related proteins, CRMP2, DDAH, MMP14
National Category
Neurology Neurosciences
URN: urn:nbn:se:uu:diva-230949DOI: 10.3389/fncel.2014.00214ISI: 000339936300001OAI: oai:DiVA.org:uu-230949DiVA: diva2:743222
Available from: 2014-09-03 Created: 2014-09-01 Last updated: 2014-09-03Bibliographically approved

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Alafuzoff, Irina
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Molecular and Morphological Pathology
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