All of the above findings demonstrated that eosinophil activation in allergic inflammation could be sensitively regulated by diverse stimuli. Besides, highly redundant functional effects and underlying signaling mechanisms were observed among different mediators. Elucidation of the mechanisms of eosinophil activation could improve our understanding of its complex and active role in the pathogenesis of allergic diseases, thereby providing biochemical basis for the development of more effective therapeutic strategies for treating the diseases. (Abstract shortened by UMI.) / Apart from the cytokines produced by T lymphoctyes, leptin, a cytokine produced by adipocytes, was also demonstrated to activate eosinophils. It was reported that the plasma levels of leptin were elevated in both obese and allergic patients. We found that leptin could activate eosinophils for survival enhancement, adhesion and migration, and secretion of cytokines and chemokines. Besides, we showed that the MAPKs and NF-kappaB pathways were involved in eosinophil adhesion, migration and mediator release induced by leptin, while Janus kinases (JAK)-signal transducers and activators of transcription (STAT) pathway was responsible for leptin-induced eosinophil survival. Our study indicated a potential correlation between obesity and exacerbation of allergic inflammation. / Eosinophilia is a hallmark pathological feature of allergic diseases and it has been targeted as a novel therapeutic strategy for allergic diseases. / In atopic dermatitis (AD), dermal infiltration of eosinophils is one of the pathological features of this disease. IL-31 is a novel Th2 cytokine reported to induce pruritus and skin dermatitis resembling human AD. Our study on the co-culture system of eosinophils and keratinocyte cell line HaCaT illustrated the production of pro-inflammatory cytokines and chemokines from the co-culture system of eosinophils and HaCaT cells, under the stimulation of IL-31. In co-culture system, surface expression of CD18 and intercellular adhesion molecule (ICAM)-1 on eosinophils and HaCaT cells was also up-regulated respectively, implying a direct interaction between the two cell types through their cell surface adhesion molecules. The interaction of eosinophils and HaCaT cells under IL-31 stimulation was shown to be mediated through MAPKs, NF-kappaB and PI3K pathways. These findings therefore elucidate the immunological roles of IL-31, eosinophils and keratinocytes in AD. / In the present study, we investigated the mechanisms of eosinophil activation induced by various stimuli including novel T helper type 2 (Th2) cytokines, adipokine, microbial products and direct interaction with tissue cells. The activation of eosinophils was studied in terms of survival enhancement, modulation of adhesion and migration, and the release of inflammatory mediators including cytokines, chemokines, granular proteins and superoxide. Using pharmacological and molecular approaches, we further investigated the intracellular signaling mechanisms regulating the eosinophil activation mediated by various stimuli. / Increasing evidence has indicated that bacterial and viral infections could intensify allergic responses. Our findings demonstrated that eosinophil activation could be elicited by microbes through toll-like receptors (TLRs), the recently discovered receptors for the recognition of conserved motifs in pathogens. We found that eosinophils could be activated by the ligands of TLR2, 5 and 7 in enhancing survival, adhesion and migration, release of pro-inflammatory cytokines, chemokines, granular proteins and superoxides. These stimulatory effects, mediated by TLR2, 5 and 7, were differentially regulated by MAPKs, NF-kappaB and phosphatidylinositol 3-kinase (PI3K) pathways. Moreover, an important finding of our study is the common involvement of focal adhesion kinase (FAK)-dependent extracellular-regulated protein kinase (ERK) phosphorylation in the signaling of TLR 2, 5 and 7, implying a special role of FAK in linking TLR signaling with MAPKs cascade in human eosinophils. Our study on microbe-induced eosinophil activation provided a potential explanation for linking infection with exacerbation of allergic diseases. / The interleukin (IL)-17 family is a newly discovered group of cytokines which was reported to be important in allergic inflammation. We studied the roles of two IL-17 family members, IL-175E/IL-25 and IL-17F on eosinophil activation. Both cytokines were found to induce the secretion of inflammatory cytokines and chemokines from eosinophils, in which IL-25 could also enhance eosinophil survival and adhesion. Besides, we found that the stimulatory effects induced by both IL-25 and IL-17F were mediated through mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-kappaB) pathways. The main source of IL-17F has recently been reported to be a novel T lymphocyte population, Th17, which is specifically driven by IL-23. An important finding of our present study was the synergistic effects of IL-17F and its potent inducer, IL-23, on cytokine release from eosinophils. Since IL-23 was produced by macrophages and dendritic cells upon microbial stimulation, the synergistic effect of IL-17F and IL-23 on eosinophil activation might imply a potential role in linking microbial infection and allergic inflammation. Our findings also provide further support to the crucial role of the IL-17 family and Th17 lymphocytes in the amplification of allergic diseases. / Cheung, Fung Yi. / Source: Dissertation Abstracts International, Volume: 69-03, Section: B, page: 1552. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (leaves 205-221). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.
| Identifer | oai:union.ndltd.org:cuhk.edu.hk/oai:cuhk-dr:cuhk_344014 |
| Date | January 2007 |
| Contributors | Cheung, Fung Yi., Chinese University of Hong Kong Graduate School. Division of Chemical Pathology. |
| Source Sets | The Chinese University of Hong Kong |
| Language | English, Chinese |
| Detected Language | English |
| Type | Text, theses |
| Format | electronic resource, microform, microfiche, 1 online resource (xviii, 221 leaves : ill.) |
| Rights | Use of this resource is governed by the terms and conditions of the Creative Commons “Attribution-NonCommercial-NoDerivatives 4.0 International” License (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
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