Interleukin 5 regulates the isoform expression of its own receptor α-subunit

The receptor for interleukin 5 (IL-5) consists of a cytokine-specific alpha chain (IL-5R alpha) and a signaling beta 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-5Ra gene splicing to generate either the membrane-anchored isoform (TM-IL-5R alpha) which associates with the common beta chain to allow IL-5 responsiveness, or a secreted, antagonist variant (SOL-IL-5R alpha), In a murine myeloid cell Line (FDC-P1), transfected with minigenes allowing expression of either IL-5R alpha variant, IL-5 itself, but not IL-3 or GM-CSF, stimulated a reversible switch toward expression of TM-IL-5R alpha. A switch from predominantly soluble isoform to TM-IL-5R alpha messenger RNA (mRNA) expression was also seen during Il-fi-driven eosinophil development from human umbilical cord blood-derived CD34(+) cells; this was accompanied by surface expression of IL-5R alpha and acquisition of functional responses to IL-5, IL-3 and GM-CSF also supported eosinophil development and up-regulation of TM-IL-5R alpha 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 alpha 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. (C) 2000 by The American Society of Hematology.