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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2525-2532
Soluble Interleukin-6 (IL-6) Receptor With IL-6 Stimulates
Megakaryopoiesis From Human CD34+ Cells Through
Glycoprotein (gp)130 Signaling
Xingwei Sui,
Kohichiro Tsuji,
Yasuhiro Ebihara,
Ryuhei Tanaka,
Kenji Muraoka,
Makoto Yoshida,
Kaoru Yamada,
Kiyoshi Yasukawa,
Tetsuya Taga,
Tadamitsu Kishimoto, and
Tatsutoshi Nakahata
From the Department of Clinical Oncology, The Institute of Medical
Science, The University of Tokyo, Tokyo, Japan; Biotechnology Research
Laboratory, Tosoh Co, Ayase, Kanagawa, Japan; and the Institute for
Molecular and Cellular Biology and Department of Medicine III, Osaka
University Medical School, Suita, Osaka, Japan.
We have recently shown that stimulation of glycoprotein (gp) 130, the membrane-anchored signal transducing receptor component of IL-6, by
a complex of human soluble interleukin-6 receptor (sIL-6R) and IL-6
(sIL-6R/IL-6), potently stimulates the ex vivo expansion as well as
erythropoiesis of human stem/progenitor cells in the presence of stem
cell factor (SCF). Here we show that sIL-6R dose-dependently enhanced
the generation of megakaryocytes (Mks) (IIbIIIa-positive cells) from
human CD34+ cells in serum-free suspension culture
supplemented with IL-6 and SCF. The sIL-6R/IL-6 complex also
synergistically acted with IL-3 and thrombopoietin (TPO) on the
generation of Mks from CD34+ cells, whereas the synergy
of IL-6 alone with TPO was barely detectable. Accordingly, the addition
of sIL-6R to the combination of SCF + IL-6 also supported a
substantial number of Mk colonies from CD34+ cells in
serum-free methylcellulose culture, whereas SCF + IL-6 in the absence
of sIL-6R rarely induced Mk colonies. The addition of monoclonal
antibodies against gp130 to the suspension and clonal cultures
completely abrogated the megakaryopoiesis induced by sIL-6R/IL-6 in the
presence of SCF, whereas an anti-TPO antibody did not, indicating that
the observed megakaryopoiesis by sIL-6R/IL-6 is a response to gp130
signaling and independent of TPO. Furthermore, human
CD34+ cells were subfractionated into two populations of
IL-6R-negative (CD34+ IL-6R ) and
IL-6R-positive (CD34+ IL-6R+) cells by
fluorescence-activated cell sorting. The CD34+
IL-6R cells produced a number of Mks as well as Mk
colonies in cultures supplemented with sIL-6R/IL-6 or TPO in the
presence of SCF. In contrast, CD34+ IL-6R+
cells generated much less Mks and lacked Mk colony forming activity under the same conditions. Collectively, the present results indicate that most of the human Mk progenitors do not express IL-6R, and that
sIL-6R confers the responsiveness of human Mk progenitors to IL-6.
Together with the presence of functional sIL-6R in human serum and
relative unresponsiveness of human Mk progenitors to IL-6 in vitro,
current results suggest that the role of IL-6 may be mainly mediated by
sIL-6R, and that the gp130 signaling initiated by the sIL-6R/ IL-6
complex is involved in human megakaryopoiesis in vivo.
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