title: Dual role of IL-21 in megakaryopoiesis and platelet homeostasis.
abstract: Gene profiling studies have indicated thatin vitrodifferentiated human megakaryocytes express the receptor for IL-21 (IL-21R), an immunostimulatory cytokine associated with inflammatory disorders and currently under evaluation in cancer therapy. The aim of this study was to investigate whether IL-21 modulates megakaryopoiesis. We first checked the expression of IL-21 receptor on human bone marrow andin vitrodifferentiated megakaryocytes. We then investigated the effect of IL-21 on thein vitrodifferentiation of human blood CD34+progenitors into megakaryocytes. Finally, we analyzed the consequences of hydrodynamic transfection-mediated transient expression of IL-21, on megakaryopoiesis and thrombopoiesis in mice. The IL-21Rα chain was expressed in human bone marrow megakaryocytes and was progressively induced duringin vitrodifferentiation of human peripheral CD34+progenitors, while the signal transducing γ chain was down-regulated. Consistently, the STAT3 phosphorylation induced by IL-21 diminished during the later stages of megakaryocytic differentiation.In vitro, IL-21 increased the number of colony-forming unit megakaryocytes generated from CD34+cells and the number of megakaryocytes differentiated from CD34+progenitors in a JAK3- and STAT3-dependent manner. Forced expression of IL-21 in mice increased the density of bi-potent megakaryocyte progenitors and bone marrow megakaryocytes, and the platelet generation, but increased platelet clearance with a consequent reduction in blood cell counts. Our work suggests that IL-21 regulates megakaryocyte development and platelet homeostasis. Thus, IL-21 may link immune responses to physiological or pathological platelet-dependent processes.
authors.affiliation: Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S 949, FMTS, F-67000, France.
authors.forename: Salima
authors.initials: S
authors.lastname: Benbarche
authors.affiliation: Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S 949, FMTS, F-67000, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Strassel
authors.affiliation: Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S 949, FMTS, F-67000, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Angénieux
authors.affiliation: Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S 949, FMTS, F-67000, France.
authors.forename: Léa
authors.initials: L
authors.lastname: Mallo
authors.affiliation: Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S 949, FMTS, F-67000, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Freund
authors.affiliation: Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S 949, FMTS, F-67000, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.affiliation: Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S 949, FMTS, F-67000, France.
authors.forename: François
authors.initials: F
authors.lastname: Lanza
authors.affiliation: Université de Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S 949, FMTS, F-67000, France henri.delasalle@efs.sante.fr.
authors.forename: Henri
authors.initials: H
authors.lastname: de la Salle
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D007378:Interleukins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000378:metabolism; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008533:Megakaryocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D010641:Phenotype; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D034061:Thrombopoiesis / Q000187:drug effects / Q000235:genetics*; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor; D053616:Janus Kinase 3; D000098546:Interleukin-21