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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2001-11-0084.
HEMATOPOIESIS
From the Departments of Pharmacology/Toxicology,
Radiation Oncology and Physiology, Medical College of Virginia Campus;
the Department of Biology, Virginia Commonwealth University; and the
Department of Internal Medicine, Hunter Holmes McGuire Veterans
Administration Medical Center, Richmond, VA; and the Division of
Cellular and Molecular Biology, Ontario Cancer Institute, University
Health Network, Toronto, Ontario, Canada.
Binding of erythropoietin (EPO) to its receptor (EPOR) on erythroid
cells induces the activation of numerous signal transduction pathways,
including the mitogen-activated protein kinase Jun-N-terminal kinase
(JNK). In an effort to understand the regulation of EPO-induced proliferation and JNK activation, we have examined the role of potential autocrine factors in the proliferation of the murine erythroleukemia cell line HCD57. We report here that treatment of these
cells with EPO induced the expression and secretion of tumor necrosis
factor alpha (TNF- Erythropoietin (EPO) is the glycoprotein hormone
necessary for the production of mature erythroid cells. Erythroid cells
at the colony-forming units-erythroid (CFU-E) to proerythroblast stage
of differentiation respond to EPO with proliferation, survival, and
terminal differentiation. EPO affects these diverse cellular events via
association with its receptor (EPOR) and subsequent activation of
numerous signal transduction pathways, which then direct the
appropriate cellular response. These pathways include Janus
kinase/signal transducers and activators of transcription (JAK2/STAT5),1-4 PI3-kinase,5,6 the
adaptor protein SHC,7-9 Src homology 2 domain-containing inositol 5-phosphatase
(SHIP),10,11 and the MAP kinase pathways Jun
N-terminal kinase (JNK)12,13 extracellular signal
related-kinase (ERK)14,15 and p38.16,17 The
ERK pathway is primarily associated with the proliferation of erythroid
cell lines.12,18,19 The kinetics of the activation of
these signals upon activation of the EPO receptor differ, however. In
the EPO-dependent murine erythroleukemia cell line HCD57, the JAK2/STAT5, ERK, and PI3-kinase pathways are activated maximally within
5 minutes of EPO binding to its receptor, followed by a decrease in the
signal to a lower basal level that is maintained as long as EPO is
present. JNK and p38, by contrast, are activated 1 to 4 hours after EPO
addition and reach maximum activation 24 hours after EPO
addition.12 Whereas much is known about the early signals
generated from EPO binding to its receptor, these long-lasting signals
that result from EPO treatment are not well understood. One possible
mechanism may be that the initial hormone triggers the autocrine or
paracrine release of a new factor that maintains the cells.
Tumor necrosis factor alpha (TNF- Our laboratory uses HCD57 cells as a model cell system for the study of
erythroid proliferation, survival, and apoptosis. These cells depend on
EPO for survival and proliferation but do not differentiate in the
presence of EPO. In an effort to elucidate the long-term EPO-induced
signals of these erythroleukemia cells, we searched for potential
autocrine factors that might promote proliferation of these cells. In
this report, we will show that whereas TNF- Reagents
Cell culture
RNAse protection analysis For RNAse protection analysis of HCD57, DA3-EPOR, and BAF3-EPOR cells, 5 × 106 cells per time point were deprived of EPO for 18 hours in the following manner: cells were washed 3 times in 10 mL media per 5 × 106 cells in IMDM media with no serum or growth factors and incubated in complete media without EPO for 18 hours prior to stimulation with either 1 U/mL EPO, 10 ng/mL stem cell factor (SCF), or 10 ng/mL TNF- for the times indicated in
the figure legends. For the inhibitor studies, the cells were
pretreated with the indicated concentrations of inhibitor for 2 hours
or 0.1% dimethyl sulfoxide (DMSO) vehicle control for 2 hours prior to
addition of EPO for 4 hours. For the human cells, following isolation
of purified CFU-E as previously described,35
2 × 107 cells were washed 3 times to eliminate EPO. The
cells were cultured in the same serum-free media without EPO, and
1 × 107 cells were collected at 1 and 6 hours
after EPO withdrawal. Cells were harvested, and total RNA was
isolated using the RNeasy RNA isolation kit (Qiagen, Valencia, CA). The
radioactive RNA probe was transcribed from the mCK-3 (Figure 1A-C),
mCK-3b (Figure 1D), or hCK-3 (for the human CFU-E) template sets (BD
Pharmingen, San Diego, CA) using 32P-UTP and an in vitro
transcription kit (BD Pharmingen) RNAse protection was carried out
using the Riboquant RNase Protection kit (BD Pharmingen) using 10 micrograms (µg) of total RNA for the mouse RNA and 5 µg for the
human CFU-E RNA, and 5.9 × 105 cpm of probe per sample.
Protected fragments were resolved on a 6% polyacrylamide, 7M urea gel
and visualized by autoradiography for 24 hours at 80°C with an
intensifying screen.
Enzyme immunoassay Triplicate samples of 1 × 105 HCD57 cells were cultured in 1 U/mL EPO or 10 nanograms (ng) SCF for 24, 48, 72, or 96 hours or with no growth factor for 96 hours as indicated in the figures. Culture media was filtered through a 0.45-mM filter and subjected to an enzyme immunoassay (EIA) using the TNF- EIA kit from
BD Pharmingen. TNF- was quantitated against a standard
curve of known concentrations of TNF- .
MTT assay HCD57 cells (1 × 105 in triplicate) were deprived of EPO as described above for 18 hours and then incubated with no additional growth factor, 1 U/mL EPO, 1 U/mL EPO with 0.01, 0.1, or 1.0 µg/mL anti-TNF- neutralizing antibody, or 1, 10, 100, and
1000 ng/mL TNF- alone for 48 hours. MTT in 1 × phosphate-buffered
saline (PBS) was added to a final concentration of 5-µg/mL, and the
cells were incubated for 4 hours at 37°C. The cells were then lysed with an equal volume of 0.2 N HCl in isopropanol, and the absorbance was read at 540 nM with a 630-nM reference filter.
Western blot analysis and in vitro kinase assay For each time point, 5 × 106 cells were used. For Western blot analysis of JNK phosphorylation, the cells were washed to deprive them of EPO for 18 hours as indicated above. The cells were then stimulated with 1 U/mL EPO or 100, 10, or 1 ng/mL TNF- for 2 hours at 37°C. The cells were lysed in 1 × sample buffer (0.05 M
Tris [tris(hydroxymethyl)aminomethane], pH = 8, 2% sodium
dodecyl sulfate, 0.1% bromophenol blue, 10% glycerol, 10%
-mercaptoethanol) and sonicated for 10 seconds each to shear the
genomic DNA. Equal volumes (40 microliters [µL]) of sample were
electrophoresed on an 8.5% sodium dodecyl sulfate-polyacrylamide
gel (SDS-PAGE) and subjected to Western blot analysis with the
phospho-specific antibodies JNK, ERK, and AKT, as previously
described.12 Specific reactive proteins were detected
using enhanced chemiluminescence (Amersham Biosciences, Piscataway,
NJ). The blot was stripped as previously described37 and
reprobed with an antibody to JNK-1 to ensure equal loading of proteins.
For the in vitro kinase assays, 5 × 106 cells per sample
were incubated in EPO in the absence or presence of anti-TNF-
antibody or IgG control antibody for 18 hours at 37°C. TNF- (100 ng/mL) was added to one sample containing anti-TNF- (Figure 4B,
lane 5) 2 hours prior to cell harvesting. Total cell extracts were
immunoprecipitated as previously described with anti-JNK-135 and subjected to an in vitro kinase assay
according to Cell Signaling Technologies' protocol for the SAPK/JNK in
vitro kinase assay. Then 20 µL of the assay was electrophoresed on a 10% acrylamide SDS-PAGE gel and subjected to Western blot analysis using a phospho-cJun-specific antibody (1:1000 dilution) overnight at
4°C. Following exposure of the phospho-cJun, the blot was stripped and then probed with the anti-JNK1 antibody to ensure equal loading of proteins.
Flow cytometry analysis of CD34+ cells Following incubation of the human CD34+ cells in the presence or absence of neutralizing TNF- antibodies, the cells were
collected, washed once in 1 × fluorescence-activated cell-sorter
scanner (FACS) buffer (1 × PBS/5% FCS/0.1% sodium azide),
resuspended in 10 µg/mL AB24G2 antibody (BD Pharmingen) to block
FC RII receptors, and incubated for 10 minutes at 4°C.
Phycoerythrin (PE)-labeled anti-glycophorin A monoclonal antibody
(clone GA-R2, BD Pharmingen) or PE-labeled mouse IgG isotype control
(clone 27-35, BD Pharmingen) was then added to a final concentration of
10 µg/mL and incubated for 30 minutes at 4°C. The cells were washed
twice with FACS buffer and resuspended in FACS buffer, and
gycophorin-A-positive cells were detected using a FACSscan flow
cytometer (Becton Dickinson, Franklin Lakes, NJ) gated on an FL-2 channel.
Colony-forming cell assays To assess murine CFU-E and burst-forming unit-erythroid (BFU-E) colony formation, 6 × 105 total murine bone marrow cells were added to 3 mL methylcellulose media (Methocult M3334, Stem Cell Technologies, Vancouver, BC, Canada) containing 3 units EPO/mL but no other cytokines in the presence or absence of 1 or 10 ng/mL TNF- .
Of these cells, 1.1 mL were plated in duplicate onto 30-mM plates and
cultured at 37°C in a moist CO2 environment. CFU-Es
were counted 2 days after the start of the experiment, and BFU-Es were
counted 8 days after the start of the experiment.
As an initial screen to detect possible autocrine secretion of
growth factors in HCD57 cells, we tested for the presence of likely
candidate cytokines using RNAse protection analysis (RPA) templates
that detect the mRNA expression of numerous cytokines. RPA of total RNA
isolated from HCD57 cells cultured in the absence or presence of EPO
revealed that TNF- The pathways upstream of EPO-induced TNF- The ability of EPO to induce TNF-
The role of TNF-
TNF-
The EPO-induced expression of TNF-
Because TNF-
TNF- TNF- Our finding that TNF- Our results in both human CD34+ cells treated with
neutralizing antibodies to TNF- TNF- In conclusion, this study demonstrates that some erythroid cell lines
have the capacity to proliferate in response to TNF-
The authors would like to thank Dr Maurice Bondurant for his assistance with RNAse protection analysis of primary murine erythroid progenitors. D.L.B is a research scientist at the National Cancer Institute of Canada.
Submitted November 28, 2001; accepted August 15, 2002.
Prepublished online as Blood First Edition Paper, August 29, 2002; DOI 10.1182/blood-2001-11-0084.
Supported by grants R01DK39781 (S.T.S.), R01HL65906 (S.T.S.), RO1 AI43433 (J.J.R.), RO1CA91839 (J.J.R.), R01CA88906 (P.D.), and R01DK52825 (P.D.) from the National Institutes of Health; grant 9804806U from the American Heart Association (S.M.J.-H.); Intramural Research Grant (IRG)-100036 from the American Cancer Society (S.M.J.-H.); grant 98-0148 (P.D.) from the Department of Defense; the Department of Veterans Affairs (E.N.D.); and Canadian Institute for Health Research (D.L.B.).
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: Stephen T. Sawyer, Department of Pharmacology/Toxicology, PO Box 980613, Richmond, VA 23298; e-mail: ssawyer{at}hsc.vcu.edu.
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