Unraveling molecular pathways that control eosinophil differentiation
Friday 23 January 2009
Prof.dr. Paul Coffer and dr. Jeffrey Beekman
Project
Eosinophils are multi-functional cells of the innate immune system that have strong immune modulatory capacity. Various pathological conditions are associated with high eosinophil numbers, however, the molecular pathways that control the production of these cells are poorly understood. Eosinophils differentiate in the bone marrow from multipotent myeloid progenitors by IL-5, a pleiotropic cytokine that belongs to the IL-5/IL-3/GM-CSF cytokine family. Of these cytokines, only IL-5 enhances eosinophil numbers suggesting that IL-5 evokes unique signals in the multipotent progenitor cell. The receptors for these cytokines are heterodimers that consist of unique alpha-chains that interact with either IL-5, GM-CSF or IL-3, and a beta-chain that is shared between these receptors. We hypothesize that IL-5-driven eosinophil differentiation results from specific signals elicited via the IL-5R alpha-chain but not via the shared beta-chain. We have previously shown that the IL-5R alpha chain specifically interacts with syntenin, and that syntenin interacts with the transcription factor SOX-4 (Science 2001; 293:1136-8). We can now show that syntenin stimulates eosinophil differentiation, and that both syntenin and SOX-4 are upregulated in eosinophil cultures but downregulated in neutrophil cultures (data unpublished). SOX-4 may regulate GATA-1 expression (a crucial transcription factor for eosinophil generation) as judged from GATA-1 promoter analysis. Together, these observations strongly suggest that the IL-5Ralpha chain-syntenin-SOX4-GATA1 axis is the important signalling pathway downstream of IL-5 that regulates eosinophil differentiation. Do you want to be part of the team that unravels the molecular pathway regulating eosinophil differentiation, this is your chance!
Research questions
Can overexpression and knockdown of SOX-4 influence eosinophil differentiation from CD34+ cord blood cells?
Can IL-5 activate GATA-1 promoter activity via SOX-4?
Can SOX-4 bind the GATA-1 promoter?
Techniques
A variety of different molecular and cellular techniques ranging from gene cloning to functional cellular assays: PCR, cloning, cell isolation, cell transfection, Western blot, retroviral transduction, transcription factor reporter assays, chromatin immunoprecipitations (ChIP)
Duration
6 or 9 months
Contact
Dr. Jeffrey Beekman, j.beekman@umcutrecht.nl
Prof.dr. Paul Coffer, p.j.coffer@umcutrecht.nl
Dr. Kristin Denzer, k.denzer@umcutrecht.nl, 088 75 576 73
More info
UMC website - Dept. of Immunology
Molecular immunology website
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