Suppressor of cytokine signalling-3 expression inhibits cytokine-mediated destruction of primary mouse and rat pancreatic islets and delays allograft rejection
2008 (English)In: Diabetologia, ISSN 0012-186X, Vol. 51, no 10, 1873-1882 p.Article in journal (Refereed) Published
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.
apoptosis, autoimmunity, diabetes, IFN gamma, IL-1, inflammation; signalling, SOCS, suppressor of cytokine signalling
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-97610DOI: 10.1007/s00125-008-1090-0ISI: 000258958400017OAI: oai:DiVA.org:uu-97610DiVA: diva2:172620