The Role of Interleukin-18 in the Immune Response to Infection.

Contains fulltext : 27417.pdf (publisher's version ) (Open Access)Interleukin-18 (IL-18), a member of the IL-1 family, is a cytokine initially described as a co-stimulus for IFN- produced in mice injected with Propionibacterium acnes and lipopolysaccharide (LPS). It is produced by many cells of the immune system like macrophages, human peripheral blood mononuclear cells, dendritic cells, epidermal cells, osteoblastic stromal cells, and cells of the central nervous system. In the presence of secondary stimulants IL-18 is able to induce large amounts of IFN- by T cells and NK cells. IL-18 displays proinflammatory effects by inducing the production of proinflammatory cytokines and chemokines. Other proinflammatory effects of IL-18 include the upregulation of adhesion molecules. IL-18 possesses broad and potent immunomodulatory properties and therefore it plays an important role in host defenses against various infectious microbes. The aim of this thesis is to assess the position of IL-18 in the activation of the innate immunity and elimination of an invading pathogen. Several aspects have been investigated in this thesis; the place of IL-18 in the activation of the cytokine network, the direct proinflammatory properties of IL-18, and the role of IL-18 in severe infections. In our studies we have shown the importance of IL-18 (and the cytokines TNF, IL-1, and IL-12) in IFN- production induced by various microbial stimuli, such as Staphylococcus epidermidis and Staphylococcus aureus, and various staphylococcal exotoxins. Moreover, we found that IL-18 displays also proinflammatory effects by increase in expression of the adhesion molecule ICAM-1. Neutralization of IL-18 during lethal endotoxemia protects mice against lethal effects of LPS. This protection is partly mediated through inhibition of IFN- production, but mechanisms involving decreased neutrophil-mediated tissue damage due to the reduction of either chemokines (E. coli LPS) or TNF (S. typhimurium LPS) synthesis by anti-IL-18 treatment may also be involved. Furthermore, IL-18 plays a protective role in the defense against disseminated candidiasis.RU Radboud Universiteit Nijmegen, 11 april 2006Promotores : Meer, J.W.M. van der, Kullberg, B.J., Dinarello, C.A. Co-promotor : Netea, M.G.148 p

The Role of Interleukin-18 in the Immune Response to Infection.

Interleukin-18 (IL-18), a member of the IL-1 family, is a cytokine initially described as a co-stimulus for IFN- produced in mice injected with Propionibacterium acnes and lipopolysaccharide (LPS). It is produced by many cells of the immune system like macrophages, human peripheral blood mononuclear cells, dendritic cells, epidermal cells, osteoblastic stromal cells, and cells of the central nervous system. In the presence of secondary stimulants IL-18 is able to induce large amounts of IFN- by T cells and NK cells. IL-18 displays proinflammatory effects by inducing the production of proinflammatory cytokines and chemokines. Other proinflammatory effects of IL-18 include the upregulation of adhesion molecules. IL-18 possesses broad and potent immunomodulatory properties and therefore it plays an important role in host defenses against various infectious microbes. The aim of this thesis is to assess the position of IL-18 in the activation of the innate immunity and elimination of an invading pathogen. Several aspects have been investigated in this thesis; the place of IL-18 in the activation of the cytokine network, the direct proinflammatory properties of IL-18, and the role of IL-18 in severe infections. In our studies we have shown the importance of IL-18 (and the cytokines TNF, IL-1, and IL-12) in IFN- production induced by various microbial stimuli, such as Staphylococcus epidermidis and Staphylococcus aureus, and various staphylococcal exotoxins. Moreover, we found that IL-18 displays also proinflammatory effects by increase in expression of the adhesion molecule ICAM-1. Neutralization of IL-18 during lethal endotoxemia protects mice against lethal effects of LPS. This protection is partly mediated through inhibition of IFN- production, but mechanisms involving decreased neutrophil-mediated tissue damage due to the reduction of either chemokines (E. coli LPS) or TNF (S. typhimurium LPS) synthesis by anti-IL-18 treatment may also be involved. Furthermore, IL-18 plays a protective role in the defense against disseminated candidiasis

Chewing khat and chronic liver disease

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Recombinant interleukin-18 protects against disseminated Candida albicans infection in mice.

Contains fulltext : 57772.pdf (publisher's version ) (Closed access)Endogenous interleukin (IL)-18 is necessary for host defense against candidiasis. Prophylactic treatment of Candida albicans-infected mice with recombinant murine (r) IL-18 decreased mortality, which was accompanied by a decreased outgrowth of yeasts in the kidneys 1 day after infection. Therapeutic administration of rIL-18 also resulted in decreased outgrowth of C. albicans in the kidneys and increased levels of interferon- gamma, both in the circulation and after in vitro stimulation of splenocytes with C. albicans. Histopathologic analysis of the kidneys showed increased inflammation and decreased growth of C. albicans in rIL-18-treated mice. In conclusion, rIL-18 improves outcome of disseminated candidiasis in mice and may prove useful as adjuvant immunotherapy of fungal infections

The role of endogenous interleukin (IL)-18, IL-12, IL-1 beta, and tumor necrosis factor-alpha in the production of interferon-gamma induced by Candida albicans in human whole-blood cultures

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Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia

Contains fulltext : 19643.pdf (publisher's version ) (Closed access

Regulation of Staphylococcus epidermidis-induced IFN-7 in whole human blood: the role of endogenous IL-18, IL-12, IL-1, and TNF

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Regulation of Staphylococcus epidermidis-induced IFN-gamma in whole human blood: the role of endogenous IL-18, IL-12, IL-1, and TNF.

Item does not contain fulltextInterleukin 12 (IL-12) and IL-18 act synergistically to stimulate interferon gamma (IFN-gamma) production; moreover, IL-1 and tumor necrosis factor (TNF) may also augment IFN-gamma synthesis. We have investigated the relative contributions of these cytokines in the production of IFN-gamma and TNF by the Gram-positive bacterium Staphylococcus epidermidis, using the specific cytokine inhibitors IL-18 binding protein (IL-18BP), IL-1 receptor antagonist (IL-1Ra), anti-IL-12 antibodies (anti-IL-12 Ab), and TNF binding protein. Inhibition of caspase-1 reduced IFN-gamma and IL-1beta levels (by 80 and 67%, respectively) when heat-killed S. epidermidis was added to whole human blood cultures. IL-18BP reduced S. epidermidis-induced IFN-gamma (77% maximal suppression). In contrast, blocking IL-1 receptors by IL-1Ra had no effect on IFN-gamma production. Blocking endogenous IL-12 and TNF reduced IFN-gamma production by 69 and 36%. S. epidermidis-induced TNF-alpha was inhibited by IL-18BP and IL-1Ra, but not anti-IL-12 Ab, whereas IL-8 production was unaffected by any of the specific cytokine blocking agents. In conclusion, S. epidermidis stimulates IFN-gamma which is IL-18, IL-12 and TNF-dependent, but IL-1 independent