Signaling mechanisms underlying IL-5-family cytokine-induced human eosinophil activation in asthma.

摘要

Eosinophils are a type of leukocyte proposed to play a role in the pathphysiology of allergic diseases, including asthma. Interleukin-5 (IL-5) -- family cytokines are known to potently activate eosinophils through induction of gene expression, enhancing inflammatory capacity, and potentiating cellular survival. Although signaling mechanisms by which inflammatory cytokines affect activation of other immune cells, exact mechanisms by which these cytokines exert effects on eosinophils are more speculative than actually confirmed. Accordingly, chapter one of my thesis addresses aspects of immune cell activation in response to inflammatory cytokines (specifically IL-5-family members, IL-7, and TSLP) and reviews literature to date delineating mechanisms by which various signaling pathways mediate cell function in other immune cell systems.;IL-5-family members are known to induce expression of Pim-1, a kinase proposed to mediate cytokine dependent survival of eosinophils and other cell types. Accordingly, chapter three of my thesis addresses intracellular signaling mechanisms by which IL-5-dependent Pim-1 expression is mediated and stimulation of Pim-1 expression in response to multiple inflammatory cytokines.;Airway eosinophils exhibit phenotypic differences when compared to blood eosinophils in terms of inflammatory capacity and survival. Signaling mechanisms underlying phenotypic differences seen between these cells have not been well studied. Chapter four of my thesis addresses signaling pathways activated downstream of IL-5-family cytokine receptors in peripheral blood eosinophils and airway eosinophils, thereby suggesting differential regulation of gene expression and other processes in these cells.;Other mediators, including IL-7 and Thymic Stromal Lymphopoietin (TSLP), are known to be produced in and play a role in allergic disease, but their effects on eosinophil biology are largely unknown. Chapters one and five of my thesis address aspects of eosinophil activation in response to these mediators and how this fits into the inflammatory environment of allergic diseases such as asthma.;Taken together, my thesis provides insight into the intracellular mechanisms regulating cytokine-induced activation of eosinophils, supporting roles for JAK/STAT signaling and MAPK signaling in mediating various aspects of eosinophil biology.