In vivo effects of cytokines on pancreatic beta-cells in models of type I diabetes dependent on CD4(+) T lymphocytes.

CD4(+) T cells can actively kill beta-cells in type I diabetes as well as help CD8(+) T cells become cytolytic. Cytokines have the potential to kill beta-cells, or upregulate Fas on beta-cells, and increase their susceptibility to FasL. We investigated the direct effects of cytokines on beta-cells in perforin-deficient non-obese diabetic (NOD) mice and NOD4.

SOCS-1 protects from virally-induced CD8 T cell mediated type 1 diabetes.

CD8(+) cytotoxic T lymphocytes (CTL) can rapidly kill beta-cells and therefore contribute to the development of type 1 diabetes (T1D). CTL-mediated beta-cell killing can occur via perforin-mediated lysis, Fas-Fas-L interaction, and the secretion of TNF-alpha or IFN-gamma. The secretion of IFN-gamma can contribute to beta-cell death directly by eliciting nitric oxide production, and indirectly by upregulating MHC class I and 'unmasking' beta-cells for recognition by CTL.

Severe pancreatitis with exocrine destruction and increased islet neogenesis in mice with suppressor of cytokine signaling-1 deficiency.

Mice with suppressor of cytokine signaling-1 (SOCS-1) deficiency die within 3 weeks of birth from a multiorgan inflammatory disease. Increased systemic levels and sensitivity of cells to the inflammatory cytokines interferon-gamma and tumor necrosis factor may contribute to the disease. Hepatitis and liver failure are thought to be the cause of the neonatal lethality in these mice.

Suppressor of cytokine signaling-1 overexpression protects pancreatic beta cells from CD8+ T cell-mediated autoimmune destruction.

In type 1 diabetes, cytokine action on beta cells potentially contributes to beta cell destruction by direct cytotoxicity, inducing Fas expression, and up-regulating class I MHC and chemokine expression to increase immune recognition. To simultaneously block beta cell responsiveness to multiple cytokines, we overexpressed suppressor of cytokine signaling-1 (SOCS-1). This completely prevented progression to diabetes in CD8(+) TCR transgenic nonobese diabetic (NOD) 8.

Virally induced inflammation triggers fratricide of Fas-ligand-expressing beta-cells.

Tissue-specific expression of Fas-ligand (Fas-L) can provide immune privilege by inducing apoptosis of "invading" lymphocytes expressing Fas. However, accelerated diabetes has been reported in transgenic mice expressing Fas-L in islets (RIP-Fas-L) as a result of Fas-dependent fratricide of beta-cells after transfer of diabetogenic clones. Here we studied whether Fas-L could protect islets from autoaggressive CD8 lymphocytes in a transgenic model of virally induced diabetes (RIP-LCMV-NP transgenic mice), in which the autoaggressive response is directed to a viral nucleoprotein (NP) expressed as a transgene in beta-cells.

IL-1 receptor deficiency slows progression to diabetes in the NOD mouse.

Proinflammatory cytokines are believed to be important in pancreatic beta-cell destruction in the development of type 1 diabetes. They act by upregulation of genes including Fas and inducible nitric oxide synthase (iNOS), which have both been shown to lead to beta-cell death in vitro. We used mice deficient in the interleukin (IL)-1 receptor (IL-1R) to assess the contribution of IL-1 to different models of diabetes.

Fas is detectable on beta cells in accelerated, but not spontaneous, diabetes in nonobese diabetic mice.

Fas (CD95) is a potential mechanism of pancreatic beta cell death in type 1 diabetes. beta cells do not constitutively express Fas but it is induced by cytokines. The hypothesis of this study is that Fas expression should be measurable on beta cells for them to be killed by this mechanism.

Suppressor of cytokine signaling-1 is a critical regulator of interleukin-7-dependent CD8+ T cell differentiation.

To determine the tissue-specific functions of SOCS-1, mice were generated in which the SOCS-1 gene could be deleted in individual tissues. A reporter gene of SOCS-1 promoter activity was also inserted. Using the reporter, high SOCS-1 expression was found at the CD4(+)CD8(+) stage in thymocyte development.

Suppressor of cytokine signaling-1 regulates signaling in response to interleukin-2 and other gamma c-dependent cytokines in peripheral T cells.

Suppressor of cytokine signaling-1 (SOCS-1) is an essential regulator of cytokine signaling. SOCS-1-/- mice die before weaning with a complex disease characterized by fatty degeneration and necrosis of the liver. This disease is mediated by interferon (IFN) gamma as neonatal mortality fails to occur in SOCS-1-/-IFNgamma-/- mice.

Suppressor of cytokine signaling-1 has IFN-gamma-independent actions in T cell homeostasis.

Suppressor of cytokine signaling (SOCS)-1 is a member of a family of proteins that negatively regulate cytokine signaling pathways. We have previously established that SOCS-1 is a key regulator of IFN-gamma signaling and that IFN-gamma is responsible for the complex inflammatory disease that leads to the death of SOCS-1-deficient mice. In this study, we provide evidence that SOCS-1 is also a critical regulator of IFN-gamma-independent immunoregulatory factors.

Constitutive activation of the SRC family kinase Hck results in spontaneous pulmonary inflammation and an enhanced innate immune response.

To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck(F/F) "knock-in" mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y(499)-residue in the Hck protein. Unlike their Hck(-/-) "loss-of-function" counterparts, Hck(F/F) "gain-of-function" mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from Hck(F/F) mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice.

Comparison of insulin secretory function in two mouse models with different susceptibility to beta-cell failure.

Type 2 diabetes is characterized by a susceptibility to beta-cell failure. However, subjects at risk of developing type 2 diabetes, such as those with obesity or a family history of diabetes, have been shown to display hyperinsulinemia. Although this hyperinsulinemia may be an adaptive response to insulin resistance, the possibility that insulin hypersecretion may be a primary defect has not been thoroughly investigated.

Interleukin-1 plus gamma-interferon-induced pancreatic beta-cell dysfunction is mediated by beta-cell nitric oxide production.

Cytokines have been implicated in pancreatic beta-cell destruction leading to type 1 diabetes. In vitro, a combination of gamma-interferon (IFN-gamma) and interleukin-1 (IL-1) stimulate inducible nitric oxide synthase (iNOS) expression in islets, and the resulting increased production of nitric oxide (NO) causes islet cell destruction. Islets contain macrophages, ductal cells, and endothelial cells that, when activated, may mediate islet cell damage by producing either NO themselves or cytokines that then stimulate NO production by beta-cells.