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Thrombopoietin stimulates colony-forming unit-megakaryocyte proliferation
and megakaryocyte maturation independently of cytokines that signal through
the gp130 receptor subunit
VC Broudy, NL Lin, N Fox, T Taga, M Saito and K Kaushansky
University of Washington, Division of Hematology, Seattle 98195-7710, USA.
Thrombopoietin (Tpo), the ligand for the c-Mpl receptor, is a major
regulator of megakaryopoiesis. Treatment of mice with Tpo raises the
platelet count fourfold within a few days. Conversely, c-mpl knock-out mice
have platelet counts that are 15% that of normal. The subunit structure of
the c-Mpl receptor is not fully understood. Some cytokines that stimulate
megakaryopoiesis (IL-6, IL-11, leukemia inhibitory factor, and oncostatin
M) bind to receptors that use gp130 as a signal transduction subunit. For
these reasons, we determined whether gp130 function was required for
Tpo-induced signal transduction. Murine marrow cells were cultured in
semi-solid media in the presence of Tpo or IL-3, with or without a
neutralizing anti-gp130 monoclonal antibody (RX187) or a soluble form of
c-Mpl receptor (soluble Mpl) that blocks Tpo bioactivity, and the numbers
of colony-forming unit-megakaryocyte (CFU-Meg) colonies were counted on day
5. Murine marrow cells were also cultured in suspension under serum-free
conditions for 5 days, and megakaryocyte DNA content was measured by flow
cytometry, as an index of nuclear maturation. The addition of RX187 did not
block Tpo-induced CFU-Meg colony growth nor CFU-Meg nuclear maturation in
suspension culture. However, IL-3-induced CFU-Meg colony growth and
megakaryocyte nuclear maturation decreased in the presence of RX187.
Soluble Mpl completely ablated Tpo-induced CFU-Meg growth, and partially
blocked IL- 3-stimulated CFU-Meg growth. Thus the effects of Tpo on
megakaryopoiesis in vitro do not depend on cytokines that signal through
gp130. Furthermore, it is unlikely that gp 130 serves as a beta chain for
the c-Mpl receptor, as Tpo signalling is unimpaired in the presence of
RX187. In contrast, the effects of IL-3 on CFU-Meg growth are mediated in
part through Tpo and through gp130-signalling cytokines.
Volume 88,
Issue 6,
pp. 2026-2032,
09/15/1996
Copyright © 1996 by The American Society of Hematology
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