title: Monocyte/macrophage dysfunctions do not impair the promotion of myelofibrosis by high levels of thrombopoietin.
abstract: Several lines of evidence indicate that the megakaryocyte/platelet lineage is crucial in myelofibrosis induction. The demonstration that NOD/SCID mice with functionally deficient monocytes do not develop fibrotic changes when exposed to thrombopoietin (TPO) also suggests an important role for monocyte/macrophages. However, in this animal model, the development of myelofibrosis is dependent on the level of TPO. This study was conducted to investigate whether NOD/SCID mice exposed to high TPO levels mediated by a retroviral vector would be refractory to the development of bone marrow fibrosis. We show that TPO and TGF-beta1 in plasma from NOD/SCID and SCID mice engrafted with TPO-overexpressing hemopoietic cells reach levels similar to the ones reached in immunocompetent mice, and all animals develop a myeloproliferative disease associated with a dense myelofibrosis at 8 wk posttransplantation. Monocytes in NOD/SCID mice are functionally deficient to secrete cytokines such as IL-1alpha in response to stimuli, even under TPO expression. Surprisingly, the plasma of these mice displays high levels of IL-alpha, which was demonstrated to originate from platelets. Together, these data suggest that completely functional monocytes are not required to develop myelofibrosis and that platelets are able, under TPO stimulation, to synthesize inflammatory cytokines, which may be involved in the pathogenesis of myelofibrosis and osteosclerosis.
authors.affiliation: Institut National de la Sante et de la Recherche Medicale (INSERM) U790, Pavillon de Recherche 1, Institut Gustave Roussy, Villejuif, France.
authors.forename: Orianne
authors.initials: O
authors.lastname: Wagner-Ballon
authors.forename: Hédia
authors.initials: H
authors.lastname: Chagraoui
authors.forename: Eric
authors.initials: E
authors.lastname: Prina
authors.forename: Micheline
authors.initials: M
authors.lastname: Tulliez
authors.forename: Geneviève
authors.initials: G
authors.lastname: Milon
authors.forename: Hana
authors.initials: H
authors.lastname: Raslova
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Villeval
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Stéphane
authors.initials: S
authors.lastname: Giraudier
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000473:pathology; D006410:Hematopoiesis / Q000276:immunology / Q000528:radiation effects; D008264:Macrophages / Q000276:immunology / Q000473:pathology*; D008297:Male; D008533:Megakaryocytes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009000:Monocytes / Q000276:immunology / Q000473:pathology*; D055728:Primary Myelofibrosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D011828:Radiation Chimera; D013154:Spleen / Q000473:pathology; D013926:Thrombopoietin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000097:blood; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation / Q000276:immunology
chemical_list: C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013926:Thrombopoietin