Interleukin-1 stimulates beta-cell necrosis and release of the immunological adjuvant HMGB1.

Background: There are at least two phases of beta-cell death during the development of autoimmune diabetes: an initiation event that results in the release of beta-cell-specific antigens, and a second, antigen-driven event in which beta-cell death is mediated by the actions of T lymphocytes. In this report, the mechanisms by which the macrophage-derived cytokine interleukin (IL)-1 induces beta-cell death are examined. IL-1, known to inhibit glucose-induced insulin secretion by stimulating inducible nitric oxide synthase expression and increased production of nitric oxide by beta-cells, also induces beta-cell death.

PPARgamma ligands induce ER stress in pancreatic beta-cells: ER stress activation results in attenuation of cytokine signaling.

Peroxisome proliferator-activated receptor (PPAR)gamma ligands are known to have anti-inflammatory properties that include the inhibition of cytokine signaling, transcription factor activation, and inflammatory gene expression. We have recently observed that increased expression of heat shock protein (HSP)70 correlates with, but is not required for, the anti-inflammatory actions of PPARgamma ligands on cytokine signaling. In this study, we provide evidence that the inhibitory actions of PPARgamma ligands on cytokine signaling are associated with endoplasmic reticulum (ER) stress or unfolded protein response (UPR) activation in pancreatic beta-cells.

PPARgamma is not required for the inhibitory actions of PGJ2 on cytokine signaling in pancreatic beta-cells.

Peroxisome proliferator-activated receptor (PPAR)gamma agonists, such as 15-deoxy-delta 12,14-prostaglandin J2 (PGJ2) and troglitazone, have been shown to elicit anti-inflammatory effects in pancreatic beta-cells that include inhibition of cytokine-stimulated inducible nitric oxide synthase (iNOS) gene expression and production of nitric oxide. In addition, these ligands impair IL-1-induced NF-kappaB and MAPK as well as IFN-gamma-stimulated signal transducer and activator of transcription (STAT)1 activation in beta-cells. The purpose of this study was to determine if PPARgamma activation participates in the anti-inflammatory actions of PGJ2 in beta-cells.

Role for c-Jun N-terminal kinase in beta-cell recovery from nitric oxide-mediated damage.

Treatment of rat islets with the cytokine IL-1 results in the inhibition of mitochondrial function and insulin secretion, events that are mediated by beta-cell expression of iNOS [inducible nitric oxide (NO) synthase] and production of NO. beta-Cells recover from the inhibitory actions of NO, produced following 24 h incubation with IL-1, on islet oxidative metabolism and insulin secretion if iNOS enzymatic activity is inhibited and the islets are cultured (in the presence of IL-1 and iNOS inhibitors) for a brief period of 8 h. Islet recovery from cytokine- and NO-mediated damage is an active process that requires new gene expression, and NO itself is one activator of this recovery process.

Inhibition of IFN-gamma -induced STAT1 activation by 15- deoxy-Delta 12,14-prostaglandin J2.

The inhibitory actions of 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ(2)) on inflammatory gene expression have been attributed to the ability of this prostaglandin to inhibit the activation of NF-kappaB. In this study, we have identified an additional signaling pathway sensitive to inhibition by PGJ(2). We show that PGJ(2) inhibits interferon (IFN)-gamma-stimulated phosphorylation and DNA-binding activity of STAT1.

Novel role for calcium-independent phospholipase A(2) in the macrophage antiviral response of inducible nitric-oxide synthase expression.

The double-stranded (ds) RNA-dependent protein kinase (PKR) is a primary regulator of antiviral responses; however, the ability of dsRNA to activate nuclear factor-kappa B (NF-kappa B) and dsRNA + interferon gamma (IFN-gamma) to stimulate inducible nitric-oxide synthase (iNOS) expression by macrophages isolated from PKR(-/-) mice suggests that signaling pathways in addition to PKR participate in antiviral activities. We have identified a novel phospholipid-signaling cascade that mediates macrophage activation by dsRNA and viral infection. Bromoenol lactone (BEL), a selective inhibitor of the calcium-independent phospholipase A(2) (iPLA(2)), prevents dsRNA- and virus-induced iNOS expression by RAW 264.

Role of interferon regulatory factor-1 in double-stranded RNA-induced iNOS expression by mouse islets.

Environmental factors, such as viral infection, have been implicated as potential triggering events leading to the initial destruction of pancreatic beta cells during the development of autoimmune diabetes. Double-stranded RNA (dsRNA), the active component of a viral infection that stimulates antiviral responses in infected cells, has been shown in combination with interferon-gamma (IFN-gamma) to stimulate inducible nitric oxide synthase (iNOS) expression and nitric oxide production and to inhibit beta cell function. Interferon regulatory factor-1 (IRF-1), the activation of which is induced by dsRNA, viral infection, and IFN-gamma, regulates the expression of many antiviral proteins, including PKR, type I IFN, and iNOS.