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HEMATOPOIESIS
From the Division of Hematology, University of
Washington School of Medicine, Seattle, WA.
Interferon (IFN)- Interferon (IFN)- Although some previous studies suggest that immune mechanisms mediate
the thrombocytopenic effects of IFN- Recently, work from other laboratories and from our own has led to the
cloning and characterization of thrombopoietin (TPO), the primary
regulator of MK and platelet production.22 Like other
members of the type 1 family of hematopoietic cytokine receptors, the
TPO receptor (c-Mpl) induces its biologic effects on ligand-induced multimerization by the activation of Janus kinase (JAK). Although a
member of the type 2 family of cell surface receptors, the IFN receptors also transduce cellular effects by the induction of JAK,
which, in turn, triggers many of the same signaling pathways initiated
by TPO and other hematopoietic cytokines. These findings suggest that
some form of cross-talk between TPO and IFN receptors might mediate the
effects of IFN- To address these issues we investigated the mechanism(s) of IFN- Reagents and cell lines
BaF3 cell culture and analysis
Marrow cell purification Marrow cells were flushed from the femurs and tibias of 8- to 10-week-old B6D2F1 mice (Jackson Laboratories, Bar Harbor, ME) that had been injected for 3 to 5 days with 2 µg rhTPO. To produce a low-density marrow cell fraction, whole marrow cells were applied to an Optiprep discontinuous gradient (density, 1.080 g/mL; Nycomed, Oslo, Norway) and subjected to 400g centrifugation for 20 minutes, and interface cells were collected, washed twice, and resuspended in phosphate-buffered saline containing 5% fetal calf serum. A lineage depleted (Lin ) marrow fraction was obtained using a
titrated mixture of rat antimouse monoclonal antibodies (7/4; Serotec,
Raleigh, NC), B220, CD5, TER119, Mac-1 (Pharmingen, San Diego, CA), and
Dynabeads M-450 (Dynal, Great Neck, NY) coated with sheep antirat IgG
as previously described.26 Finally, a purified MK
progenitor cell population was obtained by fluorescence-activated cell
sorter (FACS) purification of Lin cells. Phycoerythrin
(PE)-conjugated anti-CD41 (an IgG1) and fluorescein isothiocyanate
(FITC)-conjugated Gr-1 (IgG2b; both from Pharmingen) were added for 15 minutes on ice, and the CD41+/Gr-1 cells were
obtained by cell sorting on FACStar. Both PE-conjugated IgG1 and
FITC-conjugated rat IgG2b were used as isotype controls. Finally, to
obtain purified mature MK, whole marrow cells were placed in culture
for 3 days in the presence of 10 ng/mL murine TPO, and the cells were
applied to a discontinuous albumin gradient, as previously
described.27 The resultant cell preparation was 90% or
more pure, as assessed by acetylcholinesterase (AChE) staining.
Megakaryocyte cultures and analysis Whole bone marrow mononuclear cells were cultured at 5 or 10 × 104/0.1 mL and purified CD41+/Lin MK progenitors at from 1 to
1.5 × 103/0.1 mL in triplicate. Results from all cell
concentrations were virtually identical, allowing us to pool them from
all experiments for analysis. Cultures contained Iscove modified
Dulbecco medium supplemented with 10% fetal calf serum and
varying concentrations of rmTPO, with or without murine IFN- , and
were incubated for 4 days at 37°C in a fully humidified environment.
The cultures were then assessed for MK mass by AChE activity, for DNA
ploidy by culturing sorted CD41+/Gr-1 cells
with TPO for 3 days and staining with propidium iodide, and for cell
size by microscopic evaluation as previously
described.28,29 Additional agar-containing cultures to
enumerate colony-forming unit-MK-derived colonies were performed in
parallel using previously described methods,28 except that
whole agar plates were stained with AChE before enumeration to enhance
the accuracy of counting.
Western blotting for intracellular signaling mediators Polyclonal Mpl antiserum raised against the extracytoplasmic domain of the human Mpl protein was provided by Don Foster (ZymoGenetics), and an anti-STAT5b antibody was provided by James Ihle. Anti-phosphotyrosine mouse monoclonal antibody 4G10 and JAK2 rabbit antisera were purchased from Upstate Biotechnology (Lake Placid, NY). STAT3 polyclonal IgG and SOCS-3 antipeptide antibody were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). Dr Akihito Yoshimura (Osaka, Japan) kindly provided a polyvalent rabbit antiserum to SOCS-3. BaF3/mpl and MK lysates were prepared as described.25 Typically, 1 µg antibody was added to 500 µg protein extract for 2 hours at 20°C or overnight at 4°C, followed by protein A agarose beads (Santa Cruz Biotechnology), and the immunoprecipitate was size-fractionated by 7.5% polyacrylamide gel electrophoresis alongside prestained molecular weight markers. Proteins were transferred to nitrocellulose membranes and probed by standard techniques, typically using 1 µg/mL primary antibody 4G10, horseradish peroxidase-conjugated antimurine immunoglobulin antibody as a secondary antibody, and chemiluminescence reagents (Amersham Pharmacia, Buckinghamshire, UK).Reverse transcription-polymerase chain reaction analysis for SOCS gene expression Whole-cell RNA was obtained from BaF3/mMpl and from Lin /CD41+ MK grown for 3 days in mTPO using
the RNA preparation kit from Qiagen (Santa Clarita, CA). First-strand
cDNA was synthesized using oligo-dT primers and AMV reverse
transcriptase (Gibco) and was subjected to 24 to 30 cycles of
polymerase chain reaction (PCR) using murine SOCS-1-specific primers
(sense, 5' CACTCCGATTACCGGCGCATCAC 3'; antisense, 5'
GCTCCTGCAGCGGCCGCACG 3'), murine SOCS-3-specific primers (sense, 5'
AAAAGCGACTACCAGCTGGTGGT 3'; antisense, 5' TCTCGCCCCCAGAATAGATGTAG 3'),
or murine CIS-specific primers (sense, 5' CTGGAGCTGCCCGGGCCAGCC 3';
antisense, 5' TTTCAGGTGCACTGCAGTAGCCAC 3'), and the PCR reagents from
Promega (Madison, WI). The PCR products were visualized by ethidium
bromide staining of agarose gels, and their identities were verified by
DNA sequencing. Amplification of murine glyceraldehyde 3-phosphate
dehydrogenase (GAPDH) mRNA served as a loading control. Only
experiments in which GAPDH band densities were in the linear range
were assessed.
Statistical analysis All statistical comparisons were performed using a Student 2-tailed t test for paired values.
IFN- on TPO-induced MK development. Using whole marrow cell cultures
and AChE assays, we found that IFN- significantly inhibited
TPO-induced MK growth in a dose-dependent manner by up to 45% at 500 U/mL (Figure 1). Megakaryopoiesis was
significantly inhibited at essentially all doses of TPO tested if at
least 100 U/mL IFN- was present, a level readily attainable in
patient plasma with commonly used doses of the drug. We also performed marrow cell cultures in semisolid medium to determine whether the
effects of IFN- extended to MK colony-forming cells. As shown in
Table 1, 500 U/mL IFN- inhibited
colony formation by a statistically significant 34% to 36% at the 2 concentrations of TPO assessed.
Because both semisolid and suspension cultures of whole marrow cells
contained numerous accessory cells that could have mediated the IFN-
IFN- . To develop a model system to study the
interaction between TPO and IFN- signaling, we tested whether the
latter cytokine affected TPO-induced cell growth in BaF3/mMpl cells.
Because BaF3 is a prolymphocytic cell line, we anticipated the
expression of IFN receptors. We found that 10 to 500 U/mL IFN-
blunted TPO-induced BaF3/mMpl cell proliferation to a degree similar to
that found for MK progenitor cells (Figure
3). To test whether IFN- affected TPO
signaling, we pretreated BaF3/mMpl cells and mature MK with IFN- for
4 hours before stimulation with TPO and assessed the phosphorylation of
c-Mpl, JAK2, STAT3, and STAT5. In BaF3/mMpl cells, IFN- inhibited
the phosphorylation of TPO-induced Mpl, JAK2, and STAT5
phosphorylation, commensurate with the level of inhibition seen in the
AChE assays (Figure 4). When the
intensity of the bands shown in Figure 4 was measured by densitometry
and adjusted for the amount of each immunoprecipitated protein detected by Western blot analysis, phosphorylation of JAK2, Mpl, and STAT5 was
reduced in the presence of TPO plus IFN- to 45%, 40%, and 25%,
respectively, that seen in cells cultured in TPO alone. Curiously, STAT3 phosphorylation did not change in 3 separate experiments (data
not shown). In primary murine MK cultured in TPO plus IFN- , Mpl,
JAK2, and STAT3, phosphorylation was reduced to 40%, 75%, and 67%,
respectively, compared to cultures containing TPO alone (Figure 4B).
Because we failed to identify significant phosphorylation of mature MK
STAT5 in response to TPO in a previous study,27 the
phosphorylation of STAT5 was not investigated in the current experiments.
IFN- or TPO induced
SOCS gene expression in BaF3/mMpl cells or purified MK. Using a
specific reverse transcription (RT)-PCR assay, we found that TPO was a
poor stimulus of mRNA specific for SOCS-1 in RT-PCR assays of BaF3/mMpl
cells or purified MK (Figure 5; data not
shown). In contrast, IFN- was a potent stimulus in both cell types.
Induction of SOCS-1 mRNA was maximal at 1 hour and began to wane by 4 hours after stimulation with IFN- . In contrast, the other SOCS
protein known to inhibit hematopoietic cytokine receptor and STAT
activation, SOCS-3, was markedly induced by TPO but only poorly induced
by IFN- in BaF3/mMpl cells (Figure 6).
The addition of IFN- to TPO failed to augment the SOCS-3 response to
TPO, either at low or high concentrations of the latter. We also used
RT-PCR to evaluate CIS induction but found little difference in levels
of CIS mRNA in the presence or absence of IFN- , TPO, or both (data
not shown).
The most important findings of this report are that IFN- In the current study we found that IFN- Since the purification of IFNs and the cloning of their receptors in
the mid-1980s, numerous investigators have examined the basis by which
these cytokines exert their physiologic effects. Several studies
suggest a direct inhibitory effect of IFN on growth factor-induced
proliferation pathways. For example, IFN- The effects of IFN- Thrombopoietin is the primary regulator of MK and platelet
production.22 The hormone acts by binding to its
high-affinity cell surface receptor, c-Mpl, first recognized in altered
form as the transforming oncogene of the murine myeloproliferative leukemia virus.45 The TPO receptor is a member of the type
1 family of hematopoietic cytokine receptors.46 Much is
known of the mechanisms by which hematopoietic growth factors affect the survival, proliferation, and differentiation of cells that give
rise to all the blood lineages.47 Signal transduction in this system is initiated by ligand-induced receptor oligomerization or
conformational changes, events that induce JAK cross-phosphorylation and activation, resulting in tyrosine phosphorylation of a number of
critical intracellular substrates. Included among the downstream mediators of hematopoietic growth factor receptor activation are JAK,
STAT, MAPK, and Phosphoinositol 3 kinase (PI3K), signaling molecules
that directly impact cellular development by modifying gene expression
or the activity of molecules vital to cell proliferation and survival.
Other investigators and we27,30-34 have determined that
each of these signal transduction pathways is activated in TPO-stimulated Mpl-bearing cell lines and primary marrow-derived cells.
In contrast, IFN acts through members of the type II cytokine receptor
family, which recruits a plethora of cytoplasmic mediators to initiate
signaling cascades.48-51 Of note, many of the secondary signaling pathways common to the interleukins, hematopoietic growth factors, and protein hormones, including JAK, STAT, MAPK, and PI3K,
have been described as mediators of IFN- Recently, Jaster et al38 reported that IFN- In addition to responding to extracellular signals for growth and
metabolic activation, cells must have mechanisms to extinguish growth
factor-induced processes. Previous studies53,54 have identified a number of such mechanisms, including the down-modulation of receptor expression and the activation of phosphatases that quench
growth factor receptor-mediated signals. The importance of these
counter-regulatory pathways is illustrated by the pathologic expansion
of hematopoiesis that can occur when either process fails.55 More recently, another mechanism of growth factor
signal termination has been identified, mediated by the SOCS proteins. The cloning of a STAT-inducible gene, CIS,56 and several
additional genes that bear substantial sequence
homology37,57 has yielded a family of proteins that can
directly suppress growth factor receptor-induced signals. Because IFNs
are potent inducers of STAT1 activation, they also lead to the
production of several SOCS proteins. In turn, SOCS proteins act to
eliminate the signal that initially led to their production. On the
basis of these findings, we tested whether SOCS proteins might be
candidates to mediate IFN- Hence, we tested whether CIS, SOCS-1, or SOCS-3 was inducible in
BaF3/mMpl or murine MK treated with IFN- Several lines of evidence support the hypothesis that SOCS-1 is
responsible for IFN- We found that SOCS-3 is induced by TPO in primary murine MKs. To our knowledge, this is the first report of the responsiveness of this signaling inhibitor to TPO. Numerous cytokines have been shown to induce SOCS-3 production, including growth hormone, prolactin, leptin, IL-2, IL-10, and EPO. In fact, the most obvious physiologic effect in mice genetically engineered to eliminate SOCS-3 expression is fetal erythrocytosis, likely caused by unregulated EPO signaling.67 Thus, given the similarity of signaling pathways used by EPO and TPO, our finding that TPO also induces SOCS-3 was not unexpected. Finally, the results reported here may have broader implications. As
noted, most of the signaling pathways used by TPO are shared with a
large number of interleukins, hematopoietic growth factors, and other
cytokines, mediators exerting stimulatory and inhibitory effects on
cell development. Several of these molecules have also been
demonstrated to induce SOCS protein production, and SOCS proteins block
signaling from many stimulatory cytokines.23 Of interest,
it was recently reported that IL-10 down-modulates IFN-
We thank Dr Don Foster at ZymoGenetics for the kind gift of recombinant murine and human TPO and anti-Mpl antiserum, Dr James Ihle for the anti-STAT5b antibody, Dr Douglas Hilton for the murine SOCS-1 cDNA and antiserum to the protein, and Dr Akihito Yoshimura for the SOCS-3 cDNA and the antiserum to SOCS-1 and SOCS-3 proteins.
Submitted February 25, 2000; accepted May 12, 2000.
Supported by National Institutes of Health grants R01 CA31615 and R01 DK 49855 (K.K.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Kenneth Kaushansky, Division of Hematology, University of Washington School of Medicine, Box 357710, 1959 NE Pacific St, Seattle, WA 98195; e-mail: kkaushan{at}u.washington.edu.
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© 2000 by The American Society of Hematology.
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I. S. Hitchcock, M. M. Chen, J. R. King, and K. Kaushansky YRRL motifs in the cytoplasmic domain of the thrombopoietin receptor regulate receptor internalization and degradation Blood, September 15, 2008; 112(6): 2222 - 2231. [Abstract] [Full Text] [PDF] |
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A. Yamane, T. Nakamura, H. Suzuki, M. Ito, Y. Ohnishi, Y. Ikeda, and Y. Miyakawa Interferon-{alpha}2b-induced thrombocytopenia is caused by inhibition of platelet production but not proliferation and endomitosis in human megakaryocytes Blood, August 1, 2008; 112(3): 542 - 550. [Abstract] [Full Text] [PDF] |
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J. M. Zimmerer, G. B. Lesinski, S. V. Kondadasula, V. I. Karpa, A. Lehman, A. RayChaudhury, B. Becknell, and W. E. Carson III IFN-{alpha}-Induced Signal Transduction, Gene Expression, and Antitumor Activity of Immune Effector Cells Are Negatively Regulated by Suppressor of Cytokine Signaling Proteins J. Immunol., April 15, 2007; 178(8): 4832 - 4845. [Abstract] [Full Text] [PDF] |
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J. Matuskova, A. K. Chauhan, B. Cambien, S. Astrof, V. S. Dole, C. L. Piffath, R. O. Hynes, and D. D. Wagner Decreased Plasma Fibronectin Leads to Delayed Thrombus Growth in Injured Arterioles Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1391 - 1396. [Abstract] [Full Text] [PDF] |
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M Schmid, A Kreil, W Jessner, M Homoncik, C Datz, A Gangl, P Ferenci, and M Peck-Radosavljevic Suppression of haematopoiesis during therapy of chronic hepatitis C with different interferon {alpha} mono and combination therapy regimens Gut, July 1, 2005; 54(7): 1014 - 1020. [Abstract] [Full Text] [PDF] |
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K. W. Eriksen, V. H. Sommer, A. Woetmann, A. B. Rasmussen, C. Brender, A. Svejgaard, S. Skov, C. Geisler, and N. Odum Bi-phasic Effect of Interferon (IFN)-{alpha}: IFN-{alpha} UP- AND DOWN-REGULATES INTERLEUKIN-4 SIGNALING IN HUMAN T CELLS J. Biol. Chem., January 2, 2004; 279(1): 169 - 176. [Abstract] [Full Text] [PDF] |
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H. M. Linden and K. Kaushansky The Glycan Domain of Thrombopoietin (TPO) Acts in trans to Enhance Secretion of the Hormone and Other Cytokines J. Biol. Chem., September 13, 2002; 277(38): 35240 - 35247. [Abstract] [Full Text] [PDF] |
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M. S. Chacko and M. L. Adamo Double-Stranded RNA Decreases IGF-I Gene Expression in a Protein Kinase R-Dependent, but Type I Interferon-Independent, Mechanism in C6 Rat Glioma Cells Endocrinology, February 1, 2002; 143(2): 525 - 534. [Abstract] [Full Text] [PDF] |
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C. Bousquet, V. Chesnokova, A. Kariagina, A. Ferrand, and S. Melmed cAMP Neuropeptide Agonists Induce Pituitary Suppressor of Cytokine Signaling-3: Novel Negative Feedback Mechanism for Corticotroph Cytokine Action Mol. Endocrinol., November 1, 2001; 15(11): 1880 - 1890. [Abstract] [Full Text] [PDF] |
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C. J. Greenhalgh and D. J. Hilton Negative regulation of cytokine signaling J. Leukoc. Biol., September 1, 2001; 70(3): 348 - 356. [Abstract] [Full Text] [PDF] |
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Z. Lian, L. Wang, S. Yamaga, W. Bonds, Y. Beazer-Barclay, Y. Kluger, M. Gerstein, P. E. Newburger, N. Berliner, and S. M. Weissman Genomic and proteomic analysis of the myeloid differentiation program Blood, August 1, 2001; 98(3): 513 - 524. [Abstract] [Full Text] [PDF] |
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K. S. Wang, E. Zorn, and J. Ritz Specific down-regulation of interleukin-12 signaling through induction of phospho-STAT4 protein degradation Blood, June 15, 2001; 97(12): 3860 - 3866. [Abstract] [Full Text] [PDF] |
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