Regulation of IL-5 receptor on eosinophil progenitors in allergic inflammation: role of retinoic acid.
We and others have shown that IL-5 plays a central role in eosinophil and basophil differentiation, exerting its effects through the IL-5 receptor (IL-5R). Little is currently known concerning regulation of IL-5Ralpha gene transcription in the context of commitment of hemopoietic progenitor cells to the eosinophil and basophil lineages; recent studies have indicated that IL-5 itself can regulate IL-5Ralpha expression on mature eosinophils. We now provide evidence to indicate that IL-5 can upregulate IL-5Ralpha on bone marrow CD34+ progenitors in vitro, as we have demonstrated in vivo in atopic asthmatics. Given that all-trans retinoic acid (ATRA) is known to modulate some granulopoiesis, causing neutrophilic differentiation, we examined the effects of ATRA on eosinophil/basophil differentiation and IL-5Ralpha expression. In cultures of normal human bone marrow, ATRA selectively suppressed eosinophil/basophil differentiation. Similarly, ATRA inhibited eosinophil/basophil differentiation of cord blood CD34+ cells, while neutrophil differentiation proceeded without impediment. Most importantly, these effects of ATRA on CD34+ cells were associated with selective, dose-dependent inhibition of membrane-bound IL-5Ralpha, upregulation of soluble IL-5Ralpha transcription, but no change in GM-CSF receptor expression. These findings indicate that retinoids can differentially regulate membrane and soluble isoforms of IL-5Ralpha, and that these effects have functional consequences in vitro on eosinophil and basophil differentiation. ATRA may be of therapeutic benefit in allergic inflammatory disorders in which eosinophil differentiation and membrane-bound IL-5R are upregulated.
Denburg
J A
JA
Department of Medicine, McMaster University, Hamilton, Ont., Canada. denburg@mcmaster.ca
Sehmi
R
R
Upham
J
J
D001249:Asthma / Q000276:immunology; D001491:Basophils / Q000276:immunology; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004804:Eosinophils / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018123:Receptors, Interleukin / Q000096:biosynthesis* / Q000235:genetics; D053649:Receptors, Interleukin-5; D014212:Tretinoin / Q000494:pharmacology
D012333:RNA, Messenger; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D014212:Tretinoin