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      Functional IL-18 Is Produced by Primary Pancreatic Mouse Islets and NIT-1 Beta Cells and Participates in the Progression towards Destructive Insulitis

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          Background: Preclinical stages of type 1 diabetes are characterized by infiltrating T cells and by the peri- and intra-islet accumulation of pro-inflammatory mediators, such as IFNγ. Methods/Results: Using quantitative PCR we demonstrated that mRNA specific for the IFNγ-inducing cytokine IL-18 is upregulated in NIT-1 beta cells and intact mouse islets upon exposure to IL-1β, IFNγ and TNFα. The biological activity of IL-18 was blocked using caspase inhibitors and anti-IL-18 antibodies. Increased IL-18 expression was also detected in islets during advanced stages of insulitis and correlated with elevated transcripts for IFNγ and for the IL-18 receptor. Conclusion: Thus, beta cells produce bioactive IL-18 in the course of insulitis and actively contribute to the exacerbation of inflammation leading to their own demise.

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          Most cited references 13

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          Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme.

          The interleukin-1beta (IL-1beta) converting enzyme (ICE) processes the inactive IL-1beta precursor to the proinflammatory cytokine. ICE was also shown to cleave the precursor of interferon-gamma inducing factor (IGIF) at the authentic processing site with high efficiency, thereby activating IGIF and facilitating its export. Lipopolysaccharide-activated ICE-deficient (ICE-/-) Kupffer cells synthesized the IGIF precursor but failed to process it into the active form. Interferon-gamma and IGIF were diminished in the sera of ICE-/- mice exposed to Propionibacterium acnes and lipopolysaccharide. The lack of multiple proinflammatory cytokines in ICE-/- mice may account for their protection from septic shock.
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            Murine Macrophages Secrete Interferon γ upon Combined Stimulation with Interleukin (IL)-12 and IL-18: A Novel Pathway of Autocrine Macrophage Activation

            Interferon (IFN)-γ, a key immunoregulatory cytokine, has been thought to be produced solely by activated T cells and natural killer cells. In this study, we show that murine bone marrow– derived macrophages (BMMΦ) secrete large amounts of IFN-γ upon appropriate stimulation. Although interleukin (IL)-12 and IL-18 alone induce low levels of IFN-γ mRNA transcripts, the combined stimulation of BMMΦ with both cytokines leads to the efficient production of IFN-γ protein. The macrophage-derived IFN-γ is biologically active as shown by induction of inducible nitric oxide synthase as well as upregulation of CD40 in macrophages. Our findings uncover a novel pathway of autocrine macrophage activation by demonstrating that the macrophage is not only a key cell type responding to IFN-γ but also a potent IFN-γ–producing cell.
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              Purification and characterization of the human interleukin-18 receptor.

              Interleukin (IL)-18 was identified as a molecule that induces IFN-gamma production and enhances NK cell cytotoxicity. In this paper, we report upon the purification and characterization of human IL-18 receptor (hIL-18R). We selected the Hodgkin's disease cell line, L428, as the most strongly hIL-18R-expressing cell line based on the results of binding assays. This binding was inhibited by IL-18 but not by IL-1beta. The dissociation constant (Kd) of 125I-IL-18 binding to L428 cells was about 18.5 nM, with 18,000 binding sites/cell. After immunizing mice with L428 cells and cloning, a single monoclonal antibody (mAb) against hIL-18R was obtained (mAb 117-10C). Sequentially, hIL-18R was purified from 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS)-extracted L428 cells by wheat germ lectin-Sepharose 4B chromatography and mAb 117-10C-Sepharose chromatography. The internal amino acid sequences of hIL-18R all matched those of human IL-1 receptor-related protein (IL-1Rrp), the ligand of which was unknown to date. When expressed in COS-1 cells, the cDNA of IL-1Rrp conferred IL-18 binding properties on the cells and the capacity for signal transduction. From these results, we conclude that a functional IL-18 receptor component is IL-1Rrp.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                15 May 2002
                : 57
                : 3-4
                : 94-104
                University Children’s Hospital, and Department of Clinical and Biological Science, Basel, Switzerland
                57959 Horm Res 2002;57:94–104
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 5, References: 50, Pages: 11
                Original Paper


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