Affiliation:
1. Departments of Immunology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN 55905
Abstract
Abstract
Eosinophil activation and subsequent release of inflammatory mediators are implicated in the pathophysiology of allergic diseases. Eosinophils are activated by various classes of secretagogues, such as cytokines (e.g., IL-5), lipid mediators (e.g., platelet-activating factor (PAF)), and Ig (e.g., immobilized IgG). However, do these agonists act directly on eosinophils or indirectly through the generation of intermediate active metabolites? We now report that endogenous PAF produced by activated eosinophils plays a critical role in eosinophil functions. Human eosinophils produced superoxide when stimulated with immobilized IgG, soluble IL-5, or PAF. Pretreating eosinophils with pertussis toxin abolished their responses to these stimuli, suggesting involvement of a metabolite(s) that acts on G proteins. Indeed, PAF was detected in supernatants from eosinophils stimulated with IgG or IL-5. Furthermore, structurally distinct PAF antagonists, including CV6209, hexanolamine PAF, and Y-24180 (israpafant), inhibited IgG- or IL-5-induced superoxide production and degranulation. Previous reports indicated that exogenous PAF stimulates eosinophil eicosanoid production through formation of lipid bodies. We found in this study that IgG or IL-5 also induces lipid body formation and subsequent leukotriene C4 production mediated by endogenous PAF. Finally, inhibition of cytosolic phospholipase A2, one of the key enzymes involved in PAF synthesis, attenuated both PAF production and effector functions of eosinophils. These findings suggest that endogenous PAF plays important roles in eosinophil functional responses to various exogenous stimuli, such as cytokines and Igs. Therefore, inhibition of PAF synthesis or action may be beneficial for the treatment of eosinophilic inflammation.
Publisher
The American Association of Immunologists
Subject
Immunology,Immunology and Allergy
Reference46 articles.
1. Butterfield, J. H., K. L. Leiferman, G. J. Gleich. 1995. Eosinophil-associated diseases. M. M. Frank, and K. F. Austen, and H. N. Claman, and E. R. Unanue, eds. In Samter’s Immunologic Diseases Vol. 1: 501-527. Little Brown and Company, Boston.
2. Kita, H., C. Adolphson, and G. J. Gleich. Biology of eosinophils. 1998. In Allergy: Principles and Practice, 5th Ed. E. Middleton, Jr., C. E. Reed, E. F. Ellis, N. F. Adkinson, Jr., J. W. Yunginger, and W. W. Busse. Mosby-Year Book, St. Louis, pp. 242–260.
3. Lee, T.-c., D. J. Lenihan, B. Malone, L. L. Roddy, S. I. Wasserman. 1984. Increased biosynthesis of platelet-activating factor in activated human eosinophils. J. Biol. Chem. 259: 5526
4. Sedgwick, J. B., R. F. Vrtis, M. F. Gourley, W. W. Busse. 1988. Stimulus-dependent differences in superoxide anion generation by normal human eosinophils and neutrophils. J. Allergy Clin. Immunol. 81: 876
5. Abu-Ghazaleh, R. I., T. Fujisawa, J. Mestecky, R. A. Kyle, G. J. Gleich. 1989. IgA-induced eosinophil degranulation. J. Immunol. 142: 2393
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献