Interleukin 5 regulates the isoform expression of its own receptor <tex>$\alpha$</tex>-subunitInterleukin 5 regulates the isoform expression of its own receptor <tex>$\alpha$</tex>-subunit
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Proteinchemistry, proteomics and epigenetic signalling(PPES)
2000New York, N.Y., 2000
Blood / American Society of Hematology. - New York, N.Y.
95(2000):5, p. 1600-1607
The receptor for interleukin 5 (IL-5) consists of a cytokine-specific chain (IL-5R) and a signaling chain, which is shared with interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF). These 3 cytokines can act in eosinophil development and activation in vitro, but gene deletion or antibody blocking of IL-5 largely ablates eosinophilic responses in models of allergic disease or helminth infection. We investigated factors acting in differential IL-5R gene splicing to generate either the membrane-anchored isoform (TM-IL-5R) which associates with the common chain to allow IL-5 responsiveness, or a secreted, antagonist variant (SOL-IL-5R). In a murine myeloid cell line (FDC-P1), transfected with minigenes allowing expression of either IL-5R variant, IL-5 itself, but not IL-3 or GM-CSF, stimulated a reversible switch toward expression of TM-IL-5R. A switch from predominantly soluble isoform to TM-IL-5R messenger RNA (mRNA) expression was also seen during IL-5-driven eosinophil development from human umbilical cord blood-derived CD34+ cells; this was accompanied by surface expression of IL-5R and acquisition of functional responses to IL-5. IL-3 and GM-CSF also supported eosinophil development and up-regulation of TM-IL-5R mRNA in this system, but this was preceded by expression of IL-5 mRNA and was inhibited by monoclonal antibody to IL-5. These data suggest IL-5-specific signaling, not shared by IL-3 and GM-CSF, leading to a switch toward up-regulation of functional IL-5R and, furthermore, that IL-3 and GM-CSF-driven eosinophil development is dependent on IL-5, providing an explanation for the selective requirement of IL-5 for expansion of the eosinophil lineage.