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Antriviral effect of nicotinamide on enterovirus-infected human islets in vitro - effect on virus replication and chemokine secretion
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-96818OAI: oai:DiVA.org:uu-96818DiVA: diva2:171521
Available from: 2008-03-14 Created: 2008-03-14 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Inflammatory Mediators and Enterovirus Infections in Human Islets of Langerhans
Open this publication in new window or tab >>Inflammatory Mediators and Enterovirus Infections in Human Islets of Langerhans
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) is due to a selective loss of the insulin producing β-cells. However, the process responsible for this loss is still unknown. There is accumulating evidence that enteroviruses (EVs) are involved in T1D. In addition to direct virus-induced cytolysis, EVs could facilitate β-cell destruction by inducing inflammatory cytokines. Induction of such genes has previously been shown in EV-infected islets in vitro. Modulation of inflammatory mediators expressed in the islets could be a possible strategy to reduce β-cell destruction.

In the first paper we screened uninfected isolated human islets for genes with the potential to induce or modulate an immune response. We found that several of the genes expressed in the islets encode proteins with a powerful biological activity, such as IL-1β, IL-8, MIP-2α, MCP-1 and MIF. This indicates that the islets themselves can express several triggers of inflammation, and if expressed in vivo these mediators would probably contribute to β-cell destruction.

The vitamin B3 derivate, nicotinamide (NA), has been shown to modulate expression of factors important for coagulation and inflammatory responses. Addition of NA into isolated islet cultures resulted in a reduced expression of the pro-inflammatory chemokine MCP-1 and the coagulation activator tissue factor, suggesting that NA may have implications for both inflammatory responses and the pro-coagulant activity of islets.

We successfully isolated EVs from three newly diagnosed T1D patients. All isolates showed tropism for human islets and β-cells in vitro and clearly affected islet function. We also found that EV infection induced islet secretion of the chemokines IP-10 and MCP-1and that this induction could be blocked or reduced by addition of NA to the culture medium. Interestingly, NA also reduced viral replication and virus-induced islet destruction.

To conclude, this thesis provides new information about expression and modulation of inflammatory mediators in infected and uninfected human islets that could trigger inflammatory reactions leading to β-cell destruction. Moreover, it further strengthens the causal relationship between EV and T1D.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 51 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 316
Immunology, diabetes, islets of Langerhans, enterovirus, inflammatory mediators, cytokines, nicotinamide, Immunologi
urn:nbn:se:uu:diva-8501 (URN)978-91-554-7112-5 (ISBN)
Public defence
2008-04-05, Rudbecksalen, Rudbecklaboratoiet, Dag Hammarskjöldsväg 20, Uppsala, 09:15
Available from: 2008-03-14 Created: 2008-03-14Bibliographically approved

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