From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
Interleukin-11 Stimulates Multiple Phases of Erythropoiesis In Vitro
By Valerie F.J. Quesniaux, Steven C. Clark, Katherine Turner, and Barbara Fagg
Interleukin-I 1 (IL-I 1). a pleiotropic cytokine originally isolated from a primate bone marrow stromal cell line, has been
shown to stimulate T-celklependent B-cell maturation,
megakaryopoiesis, and various stages of myeloiddifferentiation, but to inhibit adipogenesis. Because stromal cells are
essential for the maintenance of early hematopoieticprogenitor cells in long-term culture, we investigatedthe effects of
IL-I 1 on multipotent and erythroid precursors from murine
bone marrow in vitro in suspension and semisolid cultures.
Our results show that in the presence of IL-3 or c-kit ligand
(KL), IL-11 has profound stimulatory effects on primitive
multilineagehematopoietic progenitors, pre-CFC,,w, as well
as on precursors representing various stages of erythroid
differentiation observable in vitro, including CFC,*i,
BFU-E,
and CFU-E. In addition, the combinationof KL with IL-11 also
stimulated highly proliferative erythroid progenitors that
yield remarkable macroscopic erythroblast colonies in culture. These results indicate that IL-11 is likely to play a
pivotal role in early hematopoiesis and at multiple stages of
erythropoiesis.
o 1992by The American Society of Hematology.
I
1.8 x 106 U/mg, respectively), was obtained from Genetics Institute (Cambridge, MA). Recombinant mKL was provided either as
a COS cell supernatant (Sandoz Pharma Ltd) or as purified
material by Dr S. Gillis (Immunex Inc, Seattle, WA).
Colony assays. Methylcellulose culture of normal murine bone
marrow cells (5 x lo4 cells/mL) were prepared in Iscove's modified Dulbecco's medium (IMDM) containing 4% fetal calf serum
(FCS), bovine serum fraction V, transferrin, and lipids according to
Iscove et
BFU-E-derived erythroid bursts were counted on
day 7. Macroscopic (> 1 mm) multilineage colonies comprising
erythroid, megakaryocytic, and other myeloid cells (CFC&lti),
erythroid colonies (either pure or mixed with megakaryocytes, E),
and granulocyte-macrophage (GM) colonies were counted on day
9. The colonies were identified by their morphology and were
periodically picked, spread, and stained (Wright/Giemsa) for
confirmation.
CFU-E assays were performed with 12-day murine fetal liver
(6 x l@/mL) or adult murine bone marrow cells (l@/mL) in
methylcellulose cultures containing IMDM, 4% FCS as previously
described.17 CFU-E-derived colonies were counted after 2-day
incubation at 37°C.
Replating experiments. Macroscopic compact erythroblast colonies were picked from methylcellulose cultures on day 8. The cells
were then either spread on a slide for Wright/Giemsa staining or
resuspended in IMDM, counted, and replated in secondary methyl
cellulose cultures. Replating was performed in the presence of
either (1) IL-3, IL-1, Epo, and G-CSF; (2) Epo alone; (3) IL-11
alone; or (4) in the absence of growth factor. CFU-E-like colonies
were counted after 2 days, and the plates were further observed up
to 9 days.
Suspension cultures. Suspension cultures consisted of normal
mouse bone marrow cells (105 cells/mL) cultured in 1 mL IMDM
containing a-thioglycerol, 5% FCS, and 0.1% bovine serum albumin (BSA) in 35-mm plastic bacteriologic Petri plates, according to
Iscove et
IL-1, IL-3, IL-11, and KLwere added to the cultures
as indicated. After 4 days of incubation at 3TC, the cells were
gently resuspended and harvested and the content of colonyforming cells was determined in methylcellulose cultures containing optimized concentrations of IL-3 (30 ng/mL), IL-l(l0 ng/mL),
and Epo (0.08 U/mL).
NTERLEUKIN-11 (IL-11) was originally cloned from a
primate stromal cell line, PU34, and subsequently from
the human MRC 5 cell line.' The expression cloning of
IL-11 cDNA was based on the ability of IL-11 to stimulate
the proliferation of an IL-Mependent murine plasmacytoma cell line, T1165.l Therefore, the biologic activities of
IL-11 were first investigated in assays sensitive to IL-6.
Indeed, IL-11 was shown to stimulate megakaryopoiesis by
acting on BFU-MK, CFU-MK, and on megakaryocyte
maturation in vitro's2 and this effect has been confirmed in
viv0.3,~Activities common to IL-11 and IL-6 have also been
described on lymphoid cells1>and preadipocytes.6 In addition, IL-11 was shown to promote the growth of blast
colony-forming cells in combination with IL-3 or IL-4,7,8an
effect previously described for IL-6,9 granulocyte colonystimulating factor (G-CSF),l0 and the ligand for the c-kit
encoded receptor (KL, stem cell factor, mast cell growth
factor, Steel fa~t0rll-l~).
Because stromal cells are essential for the maintenance
of early hematopoietic progenitors in long-term cultures,
we investigated the effects of IL-11 on a variety of uncommitted and committed progenitors amenable to study in
vitro. We report here the stimulatory activity of IL-11, alone
or in combination with IL-3, KL, or erythropoietin (Epo),
on all erythroid progenitors tested, including highly proliferative progenitors yielding macroscopic erythroblast colonies, as well as on multipotential progenitors. These results
indicate that IL-11 has a different spectrum of hematopoietic activities than IL-6 and that it is a potent stimulator of
erythropoiesis.
MATERIALS AND METHODS
Cytobnes. Recombinant mIL-3, hIL-lP, and hIL-6 were produced by Sandoz Pharma Ltd (Basel, Switzerland). Recombinant
hIL-11, expressed in COS-1 cells or in Escherichia coli (2 X lo6 and
From Preclinical Research, Sandoz Pharma Ltd, Basel, Switzerland; and Genetics Institute, Cambridge, MA.
Submitted April 3, 1992; accepted May 19, 1992.
Address reprint requests to Valerie F.J. Quesniaug PhD, Preclinical
Research 386/145, Sandoz Pharma Ltd, 4002, Basel, Switzerland.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C.section 1734 solely to
indicate this fact.
0 I992 by TheAmerican Society of Hematology.
0006-4971/92/8005-0024$3.00/0
1218
RESULTS
IL-11 preferentially promotes multilineage and erythroid
colonies in IL-3-containing cultures. Increasing concentra-
tions of IL-11 significantly enhanced the IL-3-dependent
colony formation measured at day 9 of incubation in the
presence of Epo (Fig 1).This effect was most prominent on
CFGUltiand erythroid colonies whose numbers increased
200% and 175%, respectively, in the presence of IL-11
(maximal at 10 to 20 ng/mL) compared with cultures
Blood, Vol80, No 5 (September 1). 1992: pp 1218-1223
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
INTERLEUKIN-11 STIMULATES ERYTHROPOIESIS
1219
IL-11 supports CFU-E maturation. To further investigate the effects of IL-11 on the late stages of erythroid
development, its ability to stimulate CFU-E-derived colonies was determined next. Figure 3 shows that IL-11 alone
does indeed stimulate, dose dependently, the development
of colonies from these late-stage erythroid precursors
obtained from either fetal liver (6,000 cells from 12-day
gestation per mL, Fig 3A) or adult bone marrow (lo5
cells/mL, Fig 3B). The number of colonies obtained was
approximately 30% of the maximum number found in
cultures stimulated with Epo alone. The stimulation of
CFU-E-derived colony formation by ILll was additive at
suboptimal Epo levels (0.02 U/mL) but combination of
IL-11 with optimal concentrations of Epo was not more
effective than Epo alone (data not shown). These findings
further indicate that IL-11 has an effect on relatively late
stages of erythroid development.
A novel type of macroscopic erythroblast colony k shown by
combinations of IL-11, KL., and Epo. To further analyze
the effects of IL-11 on primitive colony-forming progeni-
225
h
E
z
.a
200
f
K
x
K
175
0
0
0
.-K
a,
8
g
150
-0
K
125
A
100
I
I
10
I
I
20
I
I
30
I
40T
T
I
40
IL-11 concentration (ng/mL)
Fig 1. IL-11stimulation of IL-Mependent colony formation. Methylcellulose cultures of normal murine bone marrow cells (5 x l W
cells/mL) contained optimized concentrations of IL-3 (10 ng/mL) and
Epo (0.08 U/mL) plus increasingconcentrations of IL-11. Macroscopic
(>1 mm) multilineagecolonies comprising erythroid, megakaryocytic,
and other myeloid cells C
(FC
;,.,
[O]), erythroid colonies (either pure
or mixed with megakaryocytes, E; [AI) and granulocyte-macrophage
(OM; [.I) colonies were counted on day 9. The results are expressed
as the increase in colony number compared with cultures containing
no 11-11(3 2 1CFC-,
33 f 4 erythroid, and 40 2 5 OM colonies per
10 cells) and are the mean 2 SEM of four independent experiments
each with 3 to 4 plates per point. In the absence of IL-3, IL-11
stimulated <4 E and no GM colonies/105cells.
1
$
containing IL-3 alone. GM colony numbers were influenced
to a lesser extent by the addition of IL-11 (145%). IL-11
alone or in combination with Epo yielded essentially no
colonies.
IL-11 stimulates IL-J-dependent BFU-E in the absence of
ewgenous Epo. IL-11 increased the number of pure erythroid BFU-E-derived colonies obtained on day 7 of culture
in response to IL-3 and Epo (Fig 2A). Interestingly, IL-11
and IL-3 also stimulated the growth of large numbers of
BFU-E-derived colonies in the absence of Epo (Fig 2B).
This was observed consistently using either CBA/J or
C57B1/6 bone marrow cells as a source of precursors. The
cells within these colonies appeared to be at a stage of
maturation comparable to those found in colonies stimulated with Epo, suggesting that IL-11 has an effect on relatively late stages of erythroid development. In contrast, KL,
in combination with IL-11 or IL-3, was unable to promote
the growth of erythroid colonies in the absence of Epo.
401
:I
B
iod
10'
1'
0.1
T
30
e
K
'"I
o! 1
1'
10'
iod
1oob
IL-11 concentration (ng/mL)
Fig 3. Stimulation of CFU-E maturation by IL-11. CFU-€-derived
colonies were counted in methylcellulose cultures containing increasing concentrations of IL-11 plus either 12-day fetal liver cells (A) or
adult bone marrow cells (B). Results are expressed as a percentage of
the maximal stimulation obtained with 0.1 U/mL Epo (1,300 CFUW
1W fetal liver cells and 880 CFU-E/10 bone marrow cells, four and
three experiments, respectively).
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
day 11
H O . l mm
H O . l mm
40
T
I
I H0.1 mm
day 7
1
L
H 0.1 mm
301
I
mT
11-3
11-11
11-3
11-11
-
11-3
I11-11
KL
Factor combination
Fig 4. Stimulatlon of macroscopic erythroblast colonies by a
combinationof 11-11. KL, and Epo. Mathylwllulose cukums of murine
bone marrow cdk contained 0.08 U/mL Epo plus the following
factors, used eltheralone or Incombination: KL (10 pL/mL of COS cdl
supernatant), IL-11 (50 ng/mL), 11.3 (10 ng/mL), end IL-lp (10
nglml). The day 7 macroscopic erythroblast colonies (inset A)
developad into very large (>1 mm diameter) compact hemogloblnked erythroid colonies by day 11 (inset B) when they were counted.
The results are the mean f SEM of seven to elght observations from
three independent experiments.
1
125
T
100
1
4 0.1 mm
T
25
[
I
11-1
11-11
11-3
11-11
Factor combination
Fig 2. Stimulation of BFU-E-dertved colony formatton by IL-11
plus 6 3 . MahylceUulosm cultures of murine bone marrow cells
contained IL-11 (50 ng/mL) and 11-3 (10 ng/mL) either alone or In
comblnation, in the pmsence (A) or In the absence (B) of 0.08 U/mL
Epo. Erythroldburstswere counted on day 7. The results am the mean
f SEM from three independent experiments with 3 to 4 plates per
point. Epo alone stimulated no BFU-E. The insets show typical bursts
obtalned in responseto IL-11 plus IL-3 with (A) or without (B) Epo.
0
-
11-3
KL
Epo
IL-3
11-1
11-3
11-11
aO
KL
11-1
KL
Combination of Factors in Liquid Culture
KL
11-3
KL
11-11
KL
11-3
11-11
Fig 5. Increase of pluripotential precursors CFCmllnl in response to IL-11 after 4 days In
suspension culture. Normal murine bone marrowcells were incubated in liquid cukums containing 11-1 (10 ng/mL), 11-3 (10 ng/
mL), and 11-11 (50 ng/mL), alone
or in combination, (A) without or
(B) with KL (100 ng/mL). After 4
days, the liquid wltum~~
were
hawestadand the content of colony-forming cells was determined. Macroscopic CFC,,w colonies (inset) were counted on
day 9. The input number of
CFCma was 11/ lo6 fresh bone
marrow cells. Results are mean
f SEM from three Independent
experiments (four plates each).
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
INTERLEUKIN-I1 STIMULATES ERYTHROPOIESIS
tors, IL-11 was tested in combination with KL, a stromal
cell-derived cytokine found to act synergisticallywith many
different growth factors in supporting hematopoietic colony
f o r m a t i ~ n . ~ l Most
. ~ ~ , ~interestingly,
*
IL-11 plus KL and Epo
stimulated the development of large colonies with a distinct
morphology that consist predominantly of erythroblasts
(Fig 4). These colonies are round and compact, with no
evidence of the multicentric morphology typical of erythroid bursts (Fig 2), and within 8 days of culture contain
between 3 and 16 x 104 cells of early erythroblast morphology. By day 12 of culture, these colonies comprise almost
exclusively mature hemoglobinized erythroid cells (Fig 4,
inset).
If the cells from day 8 colonies are replated into secondary cultures containing a variety of growth factors (Epo plus
IL-3, IL-1, and G-CSF), only typical CFU-E-derived erythroid colonies are obtained. The plating efficiency in Epo
alone is approximately36% & 5% (n = 7), suggesting that a
large majority of the cells within these colonies are at a
comparable stage of development. When replated into
IL-11 alone, up to 23% of the number of colonies stimulated by Epo were observed (mean 13% & 3%, n = 7, with
only 3% & 1% in the absence of factor). Cell densities as
low as 1,800cells/mL (mean 3,035 -t 455, n = 7) were used
in the replating experiments.
The frequency of the BFU-E-derived colonies was not
diminished in these cultures compared with cultures supported by IL-3 plus Epo, or IL-3 and KL plus Epo (12 ? 3
BFU-E per 5 x 104 cells with KL, IL-11 plus Epo v 10 & 3
with IL-3 and Epo, and 19 -t 4 with KL and IL-3 plus Epo,
four experiments), suggesting that the progenitors yielding
the macroscopic erythroblast colonies are different from
BFU-E. The formation of total erythroid and myeloid
colonies supported by KL and Epo was enhanced by IL-11
in these cultures (2.9- 2 1.0- and 2.2- 2 O.Zfold, respectively). Multilineage colonies that are normally poorly
stimulated by KL and Epo alone were also observed in
cultures containing IL-11 plus KL and Epo, indicating that
this combination of growth factors can sustain the growth of
all hematopoietic lineages.
Early pluripotential progenitors proliferate in response to
IL-11plus IL-3 or KL. The effect of IL-11 on more
primitive pluripotential progenitors (pre-CFC,,,ulti) was then
examined in a two-step culture assay described by Iscove et
a1.I6 The pre-CFC,,,,l,i has been characterized by its ability
to divide during 4 days in liquid culture and yield daughter
cells that generate macroscopic CFC,,,,Iti in secondary
methylcellulose cultures. The proliferative response of
pre-CFC,,,,l,i (8- to 10-fold expansion) was previously reported to depend uniquely on the combination of IL-1 and
IL-319 (Fig 5A).We show here that IL-11 could effectively
replace IL-1 and, in combination with IL-3, stimulated a
10-fold increase of the number of CFC,,,uIti recovered after
liquid culture (Fig 5A). This effect was maximal at 10 to 50
ng/mL IL-11. IL-11 had no effect on its own. In addition,
IL-11 also proved effective in combination with KL in the
same system. Although neither KL alone (up to 100 ng/mL)
nor KL in combination with IL-1 significantly stimulated
the expansion of CFC,,,,l,i during 4 days in culture, combina-
1221
tion of KL with either IL-11 or IL-3 resulted in a 10-fold
increase of this cell population. Interestingly, the combination of the two stromal cell-derived factors IL-11 and I
U in
the absence of IL-3 yielded optimal results that were not
substantially improved by addition of IL-3.
DISCUSSION
In this study, IL-11 was shown to have a stimulatory effect
on a variety of murine bone marrow and fetal liver derived
progenitor cells at different stages of differentiation. The
effects of IL-11 on committed progenitors were most
pronounced within the erythroid lineage. Early in erythroid
development, IL-11 proved capable of stimulating BFU-E
when combined with IL-3, even in the absence of Epo. The
Epo independence distinguished the activity of IL-11 from
KL, which always required the addition of Epo for promoting BFU-E-derived colonies, indicating a different activity
of these two stromal factors on terminal erythroid differentiation. Later in erythroid differentiation, IL-11 alone
supported the maturation of CFU-E from fetal liver or
bone marrow cells and from a more homogenous population of cells from the day 8 macroscopic erythroblast
colonies replated at low density. This latter result suggests
that IL-11 acts directly on the terminal differentiation of
the erythroid precursors.
In addition to the traditional types of BFU-E- and
CFU-E-derived erythroid colonies, IL-11, when combined
with KL and Epo, stimulated the growth of macroscopic
erythroblast colonies containing erythroid progenitors able
to form CFU-E-like colonies with a high frequency. KL has
previously been documented to support the growth of
macroscopic blast colonies containing macrophage and
granulocyte progenitors.18 These colonies typically were
found to contain 300 to 3,000 cells after 7 days in culture in
KL alone or KL plus G-CSF.'* In contrast, the erythroid
progenitors that were stimulated in the presence of IL-11,
KL, and Epo yielded much larger colonies, typically containing 3 to 16 X 104cells on day 8 of culture. These progenitors
appear to undergo extensive proliferation without terminal
maturation through day 7, a time when BFU-E-derived
cells in the murine system are fully differentiated. They
seem to be committed to the erythroid lineage because (1)
they mature to large erythroid colonies by day 11 under
culture conditions with IL-11, KL, and Epo, which also
allowed the proliferation and full differentiation of granulocyte, macrophage, and multilineage precursors; and (2)
their progeny consisted only of typical CFU-E-derived
colonies in all culture conditions tested. On the other hand,
that these erythroid progenitors are distinct from the
typical BFU-E is suggested by the fact that (1) in the
presence of IL-11, KL, and Epo, both macroscopic colonies
of early erythroblasts and fully differentiated, hemoglobinized, BFU-E-derived colonies co-exist on day 7 in the same
cultures, and (2) the frequency of the BFU-E colony
formation was not diminished compared with cultures
supported by IL-3 plus Epo, or IL-3 and KL plus Epo.
From the potent effect of IL-11 at different stages of
erythropoiesis we would predict that this cytokine might
affect the erythroid compartment in vivo. In normal mice,
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
QUESNIAUX ET AL
1222
the administration of IL-11 (3 pg/d subcutaneously for 7 to
10 days) largely resulted in increased levels of circulating
neutrophils and platelets, with no apparent effect on
erythr0cytes.3.~However, a striking effect on erythropoiesis
was detected in lethally irradiated mice transplanted with
bone marrow cells infected with a retroviral vector producing high levels of IL-11 (C. Wood, personal communication,
March 1992). The drastically reduced hematocrits normally
seen 8 to 14 days posttransplantation in animals reconstituted with bone marrow cells infected with a control,
non-IL-11-producing virus was largely prevented when
mice were transplanted with bone marrow cells infected
with the IL-11-producing virus.
The multiplication of pre-CFGdti in suspension culture
was previously reported to require both IL-3 and IL-l.19 We
show here that IL-11 can effectively replace IL-1 in this
system. In addition, the combination of IL-11 and KL, but
not of IL-1 and KL, also yielded a 10-fold increase in the
number of CFGdti obtained from these cultures, showing
that even IL-3 could be omitted when the two stromal
factors are combined. The physiologic role of IL-3 on early
hematopoiesis has been questioned because neither IL-3
protein nor message could ever be detected in stromalsupported long-term bone marrow cultures or in the bone
marrow itself in situ. We show here that an effect of IL-3
plus IL-1 on early pluripotential progenitors can be fully
reproduced by two factors known to be produced by stromal
cells, IL-11 and KL.
Many of the activities previously described for IL-11
overlap with activities ascribed to IL-6, including the ability
to enhance IL-3-dependent colony formation by megakaryocytic progenitors18 and blast cell colony-forming cells7 and
to inhibit adipogenesis: However, IL-11 and IL-6 do not
compete for receptor binding on the plasmacytoma cell line
T10, which responds to both factors.20Our results further
distinguish the activities of the two cytokines in hematopoiesis since IL-11, but not IG6, promotes the growth of
various erythroid colonies, including a progenitor of high
proliferative capacity that yields macroscopic erythroblast
colonies.
The growth and development of blood cells in the bone
marrow microenvironment is believed to be regulated by
interactions between stromal and hematopoietic cellular
elements mediated, in part, by cytokines. Predominant
among these is KL, a stromal cell-derived cytokine demonstrated by mouse genetics to have a central role in regulating hematopoiesis, especially primitive pluripotent progenitors and progenitors of the erythroid and mast cell lineages.
Although equivalent genetic data do not exist for IL-11, our
data differentiate it from KL and implicate it as a key player
in the control of hematopoiesis. Like KL, IL-11 alone has
little effect in vitro but, when combined with either KL or
IL-3, it serves to promote the proliferation of primitive
multipotent as well as more differentiated lineage-restricted progenitors. Our results show that IL-11 has a
different spectrum of activities than other regulators known
to act on pluripotent and erythroid progenitors and that
these activities are consistent with this stromal cell-derived
cytokine having a pivotal role in the regulation of early
stages of hematopoiesis and many phases of erythropoiesis.
ACKNOWLEDGMENT
We are grateful to Barbara Sibley, JoAnn Giannotti, and James
Calvetti for help in preparing the IL-11; to Steven Gillis for the
generous gift of KL, to Susi Wehrli, Irma Ziegler, and Beatrice
Ward for their skillful technical assistance, and to Gordon Keller
and Norman Iscove for helpful discussions.
REFERENCES
1. Paul SR, Bennet F, Calvetti JA, Kelleher K, Wood CR,
OHara RM, Leary AC, Sibley B, Clark SC, Williams DA, Yang
Y C Molecular cloning of a cDNA encoding interleukin 11, a
stromal cell-derived lymphopoietic and hematopoietic cytokine.
Proc Natl Acad Sci USA 87:7512,1990
2. Bruno E, Briddell RA, Cooper RJ, Hoffman R: Effects of
recombinant interleukin 11 on human megakaryocyte progenitor
cells. Exp Hematol19:378,1991
3. Quesniaw VFJ, Mayer P, Liehl E, Turner K, Goldman SJ,
F a g B: Review of a novel hematopoietic cytokine, interleukin 11.
Int Rev Exp Pathol (in press)
4. Goldman S, Neben T, Loebelenz J, Hayes L, McCarthy K,
Stoudemire JB, Shaub R G Recombinant human interleukin 11
(rhIL-11) stimulates megakaryocytopoiesis and increases peripheral platelet number in normal and splenectomized mice. J Cell
Biochem Suppl16C:74,1992(abstr)
5. Yin T, Schendel P, Yang Y C Enhancement of in vitro
antigen-specific antibody responses by interleukin 11. J Exp Med
175:211,1992
6. Kawashima I, Oshumi J, Mita-Honjo K, Shimoda-Takano K,
Ishikawa H, Sakakibara S, Miyadai K, Takigushi Y Molecular
cloning of cDNA encoding adipogenesis inhibitory factor and
identity with interleukin-11. FEBS Lett 283:199,1991
7. Musashi M, Yang YC, Paul SR, Clark SC, Sudo T, Ogawa M
Direct and synergisticeffects of interleukin 11on murine hemopoiesis in culture. Proc Natl Acad Sci USA 88:765, 1991
8. Musashi M, Clark SC, Sudo T, Urdal DL, Ogawa M:
Synergistic interactions between interleukin-11 and interleukin-4
in support of proliferation of primitive hematopoietic progenitors
of mice. Blood 78:1448,1991
9. Ikebuchi K, Wong GG, Clark SC, Ihle JN, Hirai Y,Ogawa M:
Interleukin-6 enhancement of interleukin-3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci
USA 849035,1987
10. Ikebuchi K, Clark SC, Ihle JN, Souza LM, Ogawa M:
Granulocyte colony-stimulating factor enhances interleukin-3dependent proliferation of multi-potential hemopoietic progenitors. Proc Natl Acad Sci USA 85:3445,1988
11. Martin FH, Suggs SV, Langley KE, Lu HS, Ting J, Okino
KH, Morris CF, McNiece IK, Jacobsen FW,Mendiaz EA, Birkett
NC, Smith KA, Johnson MJ, Parker VP, Flores JC, Pate1 AC,
Fisher EF, Ejavec HO, Herrera CT,Wypych J, Sachdev RK, Pope
JA, Leslie I, Wen D, Lin CH, Cupples RL, Zsebo KM: Primary
structure and functional expression of rat and human stem cell
factor DNAs. Cell 63:203,1990
12. Williams DE, Eisenman J, Baird A, Rauch C, Van Ness K,
March CT, Park LS, Martin U, Mochizuki DY, Boswell HS,
Burgess GS, Cosman D, Lyman SD: Identification of a ligand for
the c-kit proto-oncogene. Cell 63:167,1990
13. Zsebo KM, Wypych J, McNiece IK, Lu HS, Smith KA,
Karkare SB, Sachdev RK, Yushenkoff VN, Birkett NC, Williams
LR, Satyagal VN, Tung W, Bosselman RA, Mendiaz EA, Langley
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
IMERLEUKIN-11 STIMULATES ERYTHROPOIESIS
KE: Identification, purification, and biological characterization of
hematopoietic stem cell factor from Buffalo rat liver-conditioned
medium. Cell 63:195,1990
14. Nocka K, Buck J, Levi E, Besmer P Candidate ligand for the
c-kit transmembrane kinase receptor: KL, a fibroblast-derived
growth factor stimulates mast cells and erythroid progenitors.
EMBO J 9:3287,1990
15. Tsuji K, Zsebo KM, Ogawa M Enhancement of murine
blast cell colony formation in culture by recombinant rat stem cell
factor, ligand for c-kit. Blood 781223,1991
16. Iscove NN, Shaw AR, Keller G: Net increase of pluripotential hematopoietic precursors in suspension culture in response to
IL-1 and IL-3. J Immunol1422332,1989
17. Fagg B, Roitsch C A Characterization of erythropoietin-like
activity (EpLA): A growth factor distinct from erythropoietin
1223
which stimulates late erythroid differentiation.J Cell Physiol126:1,
1986
18. Metcalf D, Nicola N A Direct proliferative actions of stem
cell factor on murine bone marrow cells in vitro: Effects of
combination with colony-stimulating factors. Proc Natl Acad Sci
USA 88:6239,1991
19. Iscove NN, Yan XQ: Precursors (pre-CFC,,,,lti) of multilineage hemopoietic colony-formingcells quantitated in vitro. Uniqueness of IL-1 requirement, partial separation from pluripotential
colony-forming cells, and correlation with long term reconstituting
cells in vivo. J Immunol145:190,1991
20. Yang YC, Yin T, McKinley D, Yang-Feng T, Paul S, Bennett
F, Sibley B, Giannoti J, Clarck S C Molecular cloning and
characterization of human interleukin-11. J Cell Biochem Suppl
15F42,1991 (abstr)
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1992 80: 1218-1223
Interleukin-11 stimulates multiple phases of erythropoiesis in vitro
VF Quesniaux, SC Clark, K Turner and B Fagg
Updated information and services can be found at:
http://www.bloodjournal.org/content/80/5/1218.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.