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Blood, 15 September 2000, Vol. 96, No. 6, pp. 2093-2099
HEMATOPOIESIS
Interferon- directly represses megakaryopoiesis by inhibiting
thrombopoietin-induced signaling through induction of
SOCS-1
Qin Wang,
Yoshitaka Miyakawa,
Norma Fox, and
Kenneth Kaushansky
From the Division of Hematology, University of
Washington School of Medicine, Seattle, WA.
Interferon (IFN)- has proven useful for treating several
clinical conditions, including chronic viral hepatitis and chronic myeloproliferative and lymphoproliferative disorders. In addition to
its well-known antiviral effects, the cytokine exerts antiproliferative effects on many cell types, helping to explain its therapeutic usefulness in these latter conditions. However, this same property accounts for several undesirable effects, including thrombocytopenia, which can interfere with the successful clinical application of IFN-. Unfortunately, the mechanisms responsible for the
myelosuppressive effects of the cytokine are incompletely understood.
The effects of IFN- on megakaryocyte (MK) development were studied.
Using several marrow cell purification techniques and quantitative
culture methods, it was found that IFN- directly inhibits
thrombopoietin (TPO)-induced MK growth. Previous studies indicated
that Janus kinase (JAK) and its substrates mediate the effects of
TPO on cellular proliferation and survival. It was found that IFN-
directly suppresses TPO-induced phosphorylation of the JAK2 substrates c-Mpl and STAT 5 in a TPO-dependent hematopoietic cell line and of Mpl
and STAT3 in primary murine MK. Moreover, IFN- induces SOCS-1
production in these cells, which has been shown to inhibit TPO-induced
cell growth. Because SOCS protein expression is induced by many
cytokines and has been reported to extinguish signaling from several
hematopoietic cytokine receptors, these results identify a molecular
mechanism responsible for cytokine receptor cross-talk.
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