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