Tissue eosinophilia is a prominent feature of allergic inflammatory diseases that may be in part mediated through the regulation of eosinophil survival at inflammatory site. T helper 2 type cytokines, such as interleukin (IL)-5, Granulocyte Macrophage Colony Stimulating Factor (GM-CSF), are the important mediators of allergic inflammation leading to prolonged survival of eosinophils. Due to the proposed central role of eosinophils in asthma and other allergic airway diseases, there is considerable interest, to determine the mechanisms that regulate eosinophil functions and accumulation. IL-12 and IL-18 attract considerable attention for their immunomodulatory roles on T helper cell subsets, and their potential to affect on eosinophil function. / The general aim of this study was to determine the effect of IL-12 and IL-18 on eosinophil functions. Results from this thesis demonstrate that eosinophils express functional receptors for IL-12 and IL-18. Acting alone or in synergy, IL-12 and IL-18 induced eosinophil apoptosis, in vitro. The apoptotic effect of IL-12 was reversed by IL-5, suggesting that IL-5 and IL-12 have counter-regulatory effects on eosinophil survival. Our regulation studies demonstrated that Phorbol-Myristate-Acetate (PMA) induced optimal expression of IL-18 and IL-12 receptors by eosinophils. IL-18 receptor expression by eosinophils was markedly increased following stimulation with interferon (IFN)-gamma, Tumor Necrosis Factor (TNF), or IL-12. Up-regulation of IL-18 receptor upon IL-12 stimulation was particularly important, which may explain IL-12 and IL-18 synergy on eosinophil apoptosis. We also investigated IL-12 and IL-18 expression by eosinophils. Eosinophils did not express IL-18. However, there was constitutive IL-12 expression by eosinophils. Release of IL-12 was also confirmed in eosinophil supernatants, which suggested an autocrine mechanism of IL-12 action on eosinophils. / Extending our understanding of the role of IL-12 and IL-18 in allergic inflammation, we have defined a novel pathway by which IL-12 and/or IL-18 may actually regulate eosinophils functions, and exert an inhibitory effect on eosinophil survival. Our findings provide critical new insights into mechanisms regulating eosinophil survival. To gain an even more detailed understanding of regulatory signals mediating eosinophil survival, we need to define the mechanisms involved in IL-12 and IL-18 signalling. We have just begun to identify the molecules involved, and these include IL-12 and IL-18 receptors. Activation via IL-12 and/or IL-18 receptor-mediated mechanisms may provide a novel strategy for reducing the numbers or inhibiting the function of these cells in allergic diseases or other diseases characterized by increased numbers of, or mediators from, eosinophils.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85633 |
| Date | January 2005 |
| Creators | Nutku, Turkan Esra |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002207777, proquestno: AAINR12919, Theses scanned by UMI/ProQuest. |
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