The long term goal of this program is to define the signalling pathways of human neutrophils and eosinophils in response to inflammatory and allergic challenge. Although the functional response of neutrophils to phagocytic challenge and chemotactic factors has been studied extensively, the stimulatory pathways are not known in detail. Less is known about the responses of neutrophils to cytokines. However, the signalling pathways in response to phagocytic challenge and cytokines appear to be different. Moreover, little is known of the signalling systems in eosinophils because they have been difficult to isolate. A basic goal of this project is to determine how neutrophils and eosinophils respond in a cell type specific manner to the same inflammatory and allergic stimuli. Of special interest is the interaction among cell types which contribute to the hyperactive response. Specifically, we will focus on stimuli which evoke products either stimulating or priming other cells. Our goal is to define intermediate steps in the signalling pathways between receptor stimulation and activation of the cytosolic phospholipase A2. The specific areas of interest are: 1) the role of phosphatidylcholine turnover by phospholipase D in neutrophil and eosinophil responses to allergic challenge; 2) the signalling pathways underlying neutrophil and eosinophil stimulation in response to cytokines (TNFa, GM-CSF) and chemotactic factors (PAF, C5a, 5-hydroxyeicosatetraenoic acid and 5-oxo-15(OH)eicosatetraenoic acid). Our preliminary studies lead to the hypothesis that phospholipase D products are required for the regulation of Raf-1 and the mitogen activated protein kinase pathways. Thus, the stimulation of these systems by the above mentioned cytokines and chemotactic factors will be a focus of this project. To accomplish these overall goals we will pursue the following specific aims: 1) to determine the role of phospholipase D in neutrophil and eosinophil signalling pathways; 2) to define the signalling pathways of neutrophils and eosinophils in response to stimuli. Overall, this project will provide a further understanding of the control of cellular function in response to allergic stimuli and identify targets for pharmacological treatment. It is envisioned that multiple signals contribute to the complete allergic response and no one mediator can be targeted to successfully ameliorate disease outcome. Therefore, multiple strategies of intervention may be required. Our studies of the interactions among cell types and mediators will provide a foundation for these strategies.
| O'Flaherty, Joseph T; Rogers, LeAnn C; Chadwell, Brad A et al. (2002) 5(S)-Hydroxy-6,8,11,14-E,Z,Z,Z-eicosatetraenoate stimulates PC3 cell signaling and growth by a receptor-dependent mechanism. Cancer Res 62:6817-9 |
| Bechoua, S; Daniel, L W (2001) Phospholipase D is required in the signaling pathway leading to p38 MAPK activation in neutrophil-like HL-60 cells, stimulated by N-formyl-methionyl-leucyl-phenylalanine. J Biol Chem 276:31752-9 |
| O'Flaherty, J T; Taylor, J S; Thomas, M J (1998) Receptors for the 5-oxo class of eicosanoids in neutrophils. J Biol Chem 273:32535-41 |
