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Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2008 (English)In: Diabetologia, ISSN 0012-186X, Vol. 51, no 10, 1873-1882 p.Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis The pro-inflammatory cytokines IL-1 and IFN gamma are critical molecules in immune-mediated beta cell destruction leading to type 1 diabetes mellitus. Suppressor of cytokine signalling (SOCS)-3 inhibits the cytokine-mediated destruction of insulinoma-1 cells. Here we investigate the effect of SOCS3 in primary rodent beta cells and diabetic animal models. Methods Using mice with beta cell-specific Socs3 expression and a Socs3-encoding adenovirus construct, we characterised the protective effect of SOCS3 in mouse and rat islets subjected to cytokine stimulation. In transplantation studies of NOD mice and alloxan-treated mice the survival of Socs3 transgenic islets was investigated. Results Socs3 transgenic islets showed significant resistance to cytokine-induced apoptosis and impaired insulin release. Neither glucose-stimulated insulin release, insulin content or glucose oxidation were affected by SOCS3. Rat islet cultures transduced with Socs3-adenovirus displayed reduced cytokine-induced nitric oxide and apoptosis associated with inhibition of the IL-1-induced nuclear factor-kappa B and mitogen-activated protein kinase (MAPK) pathways. Transplanted Socs3 transgenic islets were not protected in diabetic NOD mice, but showed a prolonged graft survival when transplanted into diabetic allogenic BALB/c mice. Conclusions/interpretation SOCS3 inhibits IL-1-induced signalling through the nuclear factor-kappa B and MAPK pathways and apoptosis induced by cytokines in primary beta cells. Moreover, Socs3 transgenic islets are protected in an allogenic transplantation model. SOCS3 may represent a target for pharmacological or genetic engineering in islet transplantation for treatment of type 1 diabetes mellitus.

Place, publisher, year, edition, pages
2008. Vol. 51, no 10, 1873-1882 p.
Keyword [en]
apoptosis, autoimmunity, diabetes, IFN gamma, IL-1, inflammation; signalling, SOCS, suppressor of cytokine signalling
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-97610DOI: 10.1007/s00125-008-1090-0ISI: 000258958400017OAI: oai:DiVA.org:uu-97610DiVA: diva2:172620
Available from: 2008-10-10 Created: 2008-10-10 Last updated: 2009-09-14Bibliographically approved
In thesis
1. Investigations of Strategies to Counteract Proinflammatory Cytokines in Experimental Type 1 Diabetes
Open this publication in new window or tab >>Investigations of Strategies to Counteract Proinflammatory Cytokines in Experimental Type 1 Diabetes
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 1 diabetes (T1D) is a chronic autoimmune disease targeted against the pancreatic β-cells. Proinflammatory cytokines are considered to play a major role in the destruction of the insulin-producing β-cells. This thesis studied strategies to counteract proinflammatory cytokines in experimental T1D. Both animal models for T1D as well as β-cell preparations exposed in vitro to putative noxious conditions were examined.

In the first study we observed that cytokine treatment of mouse pancreatic islets lacking inducible nitric oxide synthase (iNOS) induced a prolongation of the early stimulatory phase of glucose stimulated insulin secretion. Various experiments led to the conclusion that this prolonged stimulatory effect may involve the DAG/PLD/PKC pathway.

Next, we transplanted mouse islets deficient in iNOS to spontaneously diabetic NOD mice. We observed a normalization of hyperglycemia but not a delayed allograft rejection compared to transplanted wild type islets. Thus, absence of iNOS in the graft was not sufficient to prolong allograft survival.

In paper III we found that sustained glucose stimulation of rat pancreatic islets was coupled to a decreased conversion of proinsulin to insulin. Islet treatment with IL-1β was also coupled to a decreased proinsulin conversion. Islet proconvertase activity may be a target in islet damage.

In paper IV prolactin (PRL) was administered to mice in the multiple low dose streptozotocin model and we observed that PRL enhanced a Th2 response. This may contribute to the protective action by PRL in this model of autoimmune T1D.

Finally, by examining β-cells overexpressing Suppressor of cytokine signalling 3 (SOCS-3) it was found that this could inhibit IL-1β induced signalling through the NF-κB and MAPK pathways. SOCS-3 overexpression also inhibited apoptosis induced by cytokines in primary β-cells. Lastly, we demonstrated that SOCS-3 transgenic islets were protected in an allogeneic transplantation model.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 47 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 382
Type 1 diabetes, proinflammatory cytokines, SOCS-3, pancreatic islets, inducible nitric oxide synthase, insulin secretion, NOD mice, islet transplantation, proinsulin conversion, streptozotocin, prolactin
National Category
Clinical Science
urn:nbn:se:uu:diva-9306 (URN)978-91-554-7298-6 (ISBN)
Public defence
2008-10-31, B7:113a, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2008-10-10 Created: 2008-10-10Bibliographically approved

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