Abstract
IL-5Rα is a critical component of the IL-5 signaling pathway responsible for regulating the expansion of the eosinophil lineage for development of eosinophilia in allergic diseases, including asthma. IL-5Rα has two promoters, P1 and P2, both functionally active in eosinophilic cell lines. However, their differential roles and regulation during the development of authentic eosinophil progenitors remain unexplored. Human umbilical cord blood-derived CD34+progenitors under IL-5-induced eosinophil differentiation were transfected with IL-5Rα-P1 or -P2 promoter luciferase reporter vectors at various time points to assess their differential promoter activity. Chromatin immunoprecipitation (ChIP) was performed at corresponding time points to determine the dynamic occupancy of these promoters by transcription factors implicated in IL-5Rα regulation during eosinophil development. The IL-5Rα-P1 promoter is active throughout IL-5-induced eosinophil differentiation of CD34+/IL-5Rα+progenitors. However, P2 promoter activity is suddenly induced on day 7, overtaking P1 activity, before being attenuated during continued eosinophil development. Peak P2 activity coincides with a dramatic induction in expression of the predominant soluble IL-5Rα isoform mRNA. Correspondingly, quantitative ChIPs revealed that the two promoters exhibit differential occupancy by transcription factors GATA-1, PU.1 and/or the C/EBP family of transcription factors (α, β and ε). Human IL-5Rα-P1 and -P2 promoters are under differential regulation, mediated in part through dynamic and combinatorial interactions of stage-specific transcription factors. The coincidental peak in P2 promoter activity and IL-5Rα soluble isoform mRNA suggest that the IL-5-binding soluble receptor isoform is induced during eosinophil development to regulate or prevent excessive expansion of the eosinophil lineage in parasitic and allergic diseases.
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