Proinflammatory effects of interleukin 18

Culshaw, E. Shauna (2002) Proinflammatory effects of interleukin 18. PhD thesis, University of Glasgow.

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Abstract

Interleukin 18 (IL-18) was originally identified as an interferon y inducing factor in the livers of mice treated with LPS and Propionibacterium acnes. Initial studies focused on IL-18 as a Th1 driving cytokine. Subsequently, myriad effects of IL-18 have emerged, indicating a broader role to include effects on innate immunity, via activation of macrophages and NK cells. This thesis sought to further investigate the role of IL-18 in innate immune responses. IL-18 neutralisation prior to LPS challenge reduces tissue myeloperoxidase levels, implicating IL-18 at some stage in neutrophil activation. This study defines direct biological effects of IL-18 on neutrophils. IL-18 promoted in vivo migration of neutrophils, concurrently, IL-18 enhanced neutrophil adhesion molecule expression in vitro. Furthermore, IL-18 induced neutrophil cytokine and chemokine release, including IL-8, which could further promote neutrophil accumulation. Additionally, IL-18 provoked neutrophil degranulation, and primed neutrophils for enhanced respiratory burst in response to fMLP. Finally, IL-18 stimulated leukotriene synthesis by neutrophils. IL-18 promotes protective immune responses in parasitic, viral, fungal and bacterial infections. Aberrant immune responses are similarly associated with over expression of IL-18. Accordingly, elevated IL-18 is reported in rheumatoid arthritis (RA), inflammatory bowel disease (IBD), sarcoidosis, and sepsis. RA synovial fluid neutrophils are primed and activated in vivo, a process to which IL-18 may contribute. Neutrophils derived from the synovial fluid of patients with RA, exhibited enhanced cytokine release in response to IL-18, which included release of TNFalpha. Thus, IL-18 may promote joint damage via neutrophil activation. Neutralisation of IL-18 in a model of acute inflammation significantly reduced swelling and neutrophil accumulation. Given its proinflammatory effects on T cells and macrophages, targeting IL-18 is suggested as an attractive therapeutic strategy. These data suggest that effects mediated by neutrophils may be reduced. Effective neutrophil responses are paramount to clearance of gram-positive infections. XL-18-deficient mice exhibit enhanced arthritis but reduced systemic sepsis following infection with Staphylococcus aureus. Both features of this altered response may, in part, be explained by reduced neutrophil function. IL-18 promoted in vitro bactericidal activity of human neutrophils; cells derived from XL-18-deficient mice exhibited reduced killing ability in vitro. However, administration of IL-18 prior to infection with S. aureus resulted in significant mortality compared to controls, thereby suggesting that IL-18 promoted host toxicity rather than an early protective response. Further analysis revealed rapid, early IFNgamma production, elevated Toll-like receptor expression and changes in ex vivo immune responses. In contrast, post-infection administration of IL-18 substantially reduced arthritis, although no direct evidence of enhanced neutrophil bacterial killing was observed. Supplementary IL-18 promotes vaccine efficacy and may therapeutically address Th2 diseases such as asthma. These data caution addition of exogenous IL-18. Additionally, this model highlights the complex evolution of immune responses, and demonstrates discrepant consequences of intervention at different time points. IL-18 is involved in innate and adaptive responses. Although traditionally described as simple phagocytes, neutrophils have subsequently been shown to mediate adaptive responses, for example by release of cytokines and expression of MHC peptide complexes. A novel system of investigating neutrophil - T cell interactions was established. Preliminary studies to investigate neutrophil antigen presentation were strongly suggestive that neutrophils could drive Class II restricted T cell responses. The role of soluble mediators in this interaction was investigated, however preliminary experiments elucidated no role for IL-18. Data described here support a role of IL-18 in pathological inflammation, which can be perpetuated through neutrophil activation. Patients with elevated IL-18 a priori exhibit poor prognosis following gram-positive infection, similar to mice treated with IL-18 prior to S. aureus infection. Neutralising IL-18 in animal models of arthritis and inflammatory bowel disease has yielded promising results. Clearly, such manipulation of the immune system may leave the host vulnerable to infection. Therefore, the delineation of IL-18 mediated effects on neutrophils and S. aureus infection described herein requires close consideration in the context of therapeutic intervention.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Iain McInnes
Keywords: Pharmacology, Immunology
Date of Award: 2002
Depositing User: Enlighten Team
Unique ID: glathesis:2002-71240
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 10 May 2019 10:49
Last Modified: 10 May 2019 10:49
URI: http://theses.gla.ac.uk/id/eprint/71240

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