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- Niemi, MEK, et al.
(författare)
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- 2021
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swepub:Mat__t
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- Kanai, M, et al.
(författare)
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- 2023
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swepub:Mat__t
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- Momozawa, Y, et al.
(författare)
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IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1, s. 2427-
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Tidskriftsartikel (refereegranskat)abstract
- GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.
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- Rønn, SG, et al.
(författare)
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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
- 2008
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 51:10, s. 1873-1882
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Storling, J, et al.
(författare)
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Calcium has a permissive role in interleukin-1beta-induced c-jun N-terminal kinase activation in insulin-secreting cells
- 2005
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Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 146:7, s. 3026-3036
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Tidskriftsartikel (refereegranskat)abstract
- The c-jun N-terminal kinase (JNK) signaling pathway mediates IL-1β-induced apoptosis in insulin-secreting cells, a mechanism relevant to the destruction of pancreatic β-cells in type 1 and 2 diabetes. However, the mechanisms that contribute to IL-1β activation of JNK in β-cells are largely unknown. In this study, we investigated whether Ca2+ plays a role for IL-1β-induced JNK activation. In insulin-secreting rat INS-1 cells cultured in the presence of 11 mm glucose, combined pharmacological blockade of L- and T-type Ca2+ channels suppressed IL-1β-induced in vitro phosphorylation of the JNK substrate c-jun and reduced IL-1β-stimulated activation of JNK1/2 as assessed by immunoblotting. Inhibition of IL-1β-induced in vitro kinase activity toward c-jun after collective L- and T-type Ca2+ channel blockade was confirmed in primary rat and ob/ob mouse islets and in mouse βTC3 cells. Ca2+ influx, specifically via L-type but not T-type channels, contributed to IL-1β activation of JNK. Activation of p38 and ERK in response to IL-1β was also dependent on L-type Ca2+ influx. Membrane depolarization by KCl, exposure to high glucose, treatment with Ca2+ ionophore A23187, or exposure to thapsigargin, an inhibitor of sarco(endo)plasmic reticulum Ca2+ ATPase, all caused an amplification of IL-1β-induced JNK activation in INS-1 cells. Finally, a chelator of intracellular free Ca2+ [bis-(o-aminophenoxy)-N,N,N′,N′-tetraacetic acid-acetoxymethyl], an inhibitor of calmodulin (W7), and inhibitors of Ca2+/calmodulin-dependent kinase (KN62 and KN93) partially reduced IL-1β-stimulated c-jun phosphorylation in INS-1 or βTC3 cells. Our data suggest that Ca2+ plays a permissive role in IL-1β activation of the JNK signaling pathway in insulin-secreting cells.
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