Aims/hypothesis: Beta cell inflammation and cytokine-induced toxicity are central to autoimmune diabetes development. Lipid mediators generated upon lipoxygenase (LO) activation can participate in inflammatory pathways. 12LO-deficient mice are resistant to streptozotocin-induced diabetes. This study sought to characterise the cellular processes involving 12LO-activation lipid inflammatory mediator production in cytokine-treated pancreatic beta cells. Methods: Islets and beta cell lines were treated with a combination of IL-1β, IFN-γ and TNF-α, or the 12LO product 12(S)-hydroxyeicosatetraenoic acid (HETE). Insulin secretion was measured using an enzyme immunoassay, and cell viability was evaluated using an in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay. 12LO activity was evaluated and 12LO protein levels were determined using immunoblotting with a selective leucocyte type 12LO antibody. Cellular localisation of 12LO was evaluated using immunocytochemistry. Results: Basal expression of leucocyte type 12LO protein was found in human and mouse islets and in several rodent beta cell lines. In mouse β-TC3 cells, and in human islets, cytokines induced release of 12-HETE within 30 min. Cytokine addition also induced a rapid translocation of 12LO protein from the cytosol to the nucleus of β-TC3 cells as shown by subcellular fractionation and immunostaining. Cytokine-induced cell death and inhibition of insulin secretion were partially reversed by baicalein, a 12LO inhibitor. 12(S)-HETE inhibited β-TC3 cell insulin release in a time-and concentration-dependent manner. Incubating β-TC3 cells with 100 nmol/l of 12(S)-HETE resulted in a 57% reduction in basal insulin release (6 h), and a 17% increase in cell death (18 h) as compared with untreated cells. 12(S)-HETE activated the stress-activated protein kinase c-Jun N-terminal kinase and p38 within 15 min, as judged by increased kinase protein phosphorylation. Conclusions/interpretation: The data suggest that inflammatory cytokines rapidly activate 12LO and show for the first time that cytokines induce 12LO translocation. The effects of 12-HETE on insulin secretion, cytotoxicity and kinase activation were similar to the effects seen with cytokines. The results provide mechanistic information of cytokine-induced toxic effects on pancreatic beta cells and support the hypothesis that blocking 12LO activation could provide a new therapeutic way to protect pancreatic beta cells from autoimmune injury.
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Kampala and part of Wakiso districts and included children (0-14 years) and adolescents (15-19 years). The data was analysed using SPSS. Findings: A total of 752 patients, 71.7% (n¼539) were children (0-14 years) and 29.3% (n¼213) were adolescents (15-19 years) diagnosed with cancer between January, 2009 and December, 2014. Among the children, Hodgkin lymphoma was 21%, 12% Kaposi Sarcoma, 9% nephroblastoma, 7% retinoblastoma, 11% unspecified malignancies and 40% others. Among the adolescents, 20% were Kaposi Sarcoma, 18% Non-Hodgkin lymphoma, 8% Hodgkin lymphoma, 7% Hodgkin Lymphoma, 6% Chronic Myeloid leukaemia and 41% other malignancies. The age adjusted incidence per one million of childhood malignancies were; Non-Hodgkin Lymphoma (26), Kaposi Sarcoma (14.95), Nephroblastoma (9.2). Age Adjusted Incidence Rate of adolescent malignancies were; Kaposi Sarcoma (10.05), Non-Hodgkin Lymphoma (4.31), Hodgkin lymphoma (3.59). Retiniblastoma and nephroblastoma were found in only children.
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