Interleukin 5 regulates the isoform expression of its own receptor alpha-subunit.
The receptor for interleukin 5 (IL-5) consists of a cytokine-specific alpha chain (IL-5Ralpha) 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-5Ralpha gene splicing to generate either the membrane-anchored isoform (TM-IL-5Ralpha) which associates with the common beta chain to allow IL-5 responsiveness, or a secreted, antagonist variant (SOL-IL-5Ralpha). In a murine myeloid cell line (FDC-P1), transfected with minigenes allowing expression of either IL-5Ralpha variant, IL-5 itself, but not IL-3 or GM-CSF, stimulated a reversible switch toward expression of TM-IL-5Ralpha. A switch from predominantly soluble isoform to TM-IL-5Ralpha 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-5Ralpha and acquisition of functional responses to IL-5. IL-3 and GM-CSF also supported eosinophil development and up-regulation of TM-IL-5Ralpha 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-5Ralpha 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. (Blood. 2000;95:1600-1607)
Tavernier
J
J
Flanders Interuniversity Institute for Biotechnology and Department of Respiratory Diseases, University of Ghent, Belgium. jan.tavernier@rug.ac.be
Van der Heyden
J
J
Verhee
A
A
Brusselle
G
G
Van Ostade
X
X
Vandekerckhove
J
J
North
J
J
Rankin
S M
SM
Kay
A B
AB
Robinson
D S
DS
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D015848:Interleukin-5 / Q000494:pharmacology*; D011487:Protein Conformation; D020033:Protein Isoforms / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D053649:Receptors, Interleukin-5; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis
D007377:Interleukin-3; D015848:Interleukin-5; D020033:Protein Isoforms; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D011993:Recombinant Fusion Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor