Inflammatory mediators expressed in human islets of Langerhans: implications for islet transplantation

Johansson, Ulrika; Olsson, Anna-Karin; Gabrielsson, Susanne; Nilsson, Bo; Korsgren, Olle

doi:10.1016/s0006-291x(03)01392-5

Cited by 154 publications

(129 citation statements)

References 41 publications

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“…Human pancreatic islets Human pancreatic islets were isolated from three donors (one female and two males) and purified at the Uppsala University Hospital (coordinator, Prof. Olle Korsgren) as previously described [15], with the consent of the ethics committee of Uppsala University. The donor age varied between 45 and 74 years and cold ischaemia time between 6 h and 8 h 54 min.…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

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Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

et al. 2005

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Aims/hypothesis: It is thought that enterovirus infections initiate or facilitate the pathogenetic processes leading to type 1 diabetes. Exposure of cultured human islets to cytolytic enterovirus strains kills beta cells after a protracted period, suggesting a role for secondary virusinduced factors such as cytokines. Methods: To clarify the molecular mechanisms involved in virus-induced beta cell destruction, we analysed the global pattern of gene expression in human islets. After 48 h, RNA was extracted from three independent human islet preparations infected with coxsackievirus B5 or exposed to interleukin 1β (50 U/ml) plus interferon γ (1,000 U/ml), and gene expression profiles were analysed using Affymetrix HG-U133A gene chips, which enable simultaneous analysis of 22,000 probe sets. Results: As many as 13,077 genes were detected in control human islets, and 945 and 1293 single genes were found to be modified by exposure to viral infection and the indicated cytokines, respectively. Four hundred and eighty-four genes were similarly modified by the cytokines and viral infection. Conclusions/ interpretation: The large number of modified genes observed emphasises the complex responses of human islet cells to agents potentially involved in insulitis. Notably, both cytokines and viral infection significantly (p<0.02) increased the expression of several chemokines, the cytokine IL-15 and the intercellular adhesion molecule ICAM-1, which might contribute to the homing and activation of mononuclear cells in the islets during infection and/or an early autoimmune response. The present results provide novel insights into the molecular mechanisms involved in viral-and cytokine-induced human beta cell dysfunction and death.

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Section: Subjects Materials and Methodsmentioning

confidence: 99%

“…IFIT1: 2 and 4 interferon-induced protein with tetratricopeptide repeats 1, 2 and 4 . IFITM1: interferon-induced transmembrane protein 1 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) . IFNB1: interferon β1, fibroblast .…”

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confidence: 99%

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

et al. 2005

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“…Thus, VEGF may be expected to ameliorate damage to islets in the immediate post-transplant period. Array technology has shown that isolated human islets express VEGF [25], and it has been reported that VEGF protein is co-expressed with insulin [26], as in the rat. The production of VEGF receptors by human islets has not been characterised in detail.…”

Section: Introductionmentioning

confidence: 99%

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

et al. 2007

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Aims/hypothesis Rapamycin, part of the immunosuppressive regimen of the Edmonton protocol, has been shown to inhibit vascular endothelial growth factor (VEGF) production and VEGF-mediated survival signalling in tumour cell lines. This study investigates the survival-promoting activities of VEGF in human islets and the effects of rapamycin on islet viability.Materials and methods Levels of VEGF and its receptors in isolated human islets and whole pancreas was determined by western blotting and immunostaining. Islet viability following VEGF or immunosuppressive drug treatment was determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Islet VEGF release was measured by ELISA. Mouse islets infected with an adenovirus expressing the gene for VEGF were transplanted syngeneically into streptozotocin-induced diabetic mice, with blood glucose levels measured three times per week. Results Isolated human islets produced multiple isoforms of VEGF and VEGF receptors 1, 2 and 3 and the coreceptor neuropilin 1. Exogenous VEGF (10 ng/ml) prevented human islet death induced by serum starvation, which suggests that VEGF can act as a survival factor for human islets. Transplantation of mouse islets infected with a VEGF-expressing adenovirus in a syngeneic model, improved glycaemic control at day 1 post-transplantation (p< 0.05). Rapamycin at 10 and 100 ng/ml significantly reduced islet VEGF release (by 37±4% and 43±6%, respectively; p<0.05) and at 100 ng/ml reduced islet viability (by 36±9%) and insulin release (by 47±7%, all vs vehicle-treated controls; p<0.05). Tacrolimus had no effect on islet VEGF release or viability. Conclusions/interpretation Our data suggest that rapamycin may have deleterious effects on islet survival posttransplantation, both through a direct effect on islet viability and indirectly through blockade of VEGF-mediated revascularisation.

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“…Indeed, porcine islets that have been cultured for at least 24 h are significantly better at reversing hyperglycaemia when transplanted into diabetic nude mice compared with freshly isolated islets [19]. In addition, there is a much higher relative expression of inflammatory genes during the immediate post-isolation period when compared with islets cultured for 1 week [20]. Culturing islets also provides an opportunity for therapies aimed at improving islet survival, inducing islet expansion, and reducing islet immunogenicity.…”

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confidence: 99%

Autocrine insulin action activates Akt and increases survival of isolated human islets

et al. 2006

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Aims/hypothesis The phosphatidylinositol 3-kinase (PI3K)/ Akt pathway plays a critical role in promoting the survival of pancreatic beta cells. Akt becomes activated in isolated human islets following overnight culture despite significant levels of cell death. The aim of the current study was to identify the cause of the observed increase in Akt phosphorylation in isolated islets. We hypothesised that a factor secreted by the islets in culture was acting in an autocrine manner to activate Akt. Methods In order to identify the stimulus of the PI3K/Akt pathway in culture, we examined the effects of different culture conditions on Akt phosphorylation and islet survival during the immediate post-isolation period. Results We demonstrated that islet-conditioned medium induced Akt phosphorylation in freshly isolated human islets, whereas frequent medium replacement decreased Akt phosphorylation. Following overnight culture, islet-conditioned medium contained significantly elevated levels of insulin, indicating that insulin may be responsible for the observed increase in Akt phosphorylation. Indeed, treatment with an anti-insulin antibody or with inhibitors of insulin receptor/IGF receptor 1 kinase activity suppressed Akt phosphorylation, leading to decreased islet survival. In addition, dispersion of islets into single cells also suppressed Akt phosphorylation and induced islet cell death, indicating that islet integrity is also required for maximal Akt phosphorylation. Conclusions/interpretation Our findings demonstrate that insulin acts in an autocrine manner to activate Akt and mediate the survival of isolated human islets. These findings provide new information on how culturing islets prior to transplantation may be beneficial to their survival by allowing for autocrine activation of the pro-survival Akt pathway.

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Inflammatory mediators expressed in human islets of Langerhans: implications for islet transplantation

Cited by 154 publications

References 41 publications

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

Global profiling of coxsackievirus- and cytokine-induced gene expression in human pancreatic islets

Vascular endothelial growth factor as a survival factor for human islets: effect of immunosuppressive drugs

Autocrine insulin action activates Akt and increases survival of isolated human islets

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