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Mechanism
Regulate
Physiologic
of Action
of Serum
Factors
That
Granulopoiesis
In Vitro:
Possible
Role
of Serum-Inhibiting
Activity
By Fraser
L. Baker
and
The purpose
of this study was to invostigate mechanisms
of action and in vivo relationships
of serum
factors
that regulate
granulopoiesis
in vitro.
Granulopoiosis
involves
interactions
between
stimulating
and proliferating
cells,
and in order
to
determine
mechanisms
of action
it is
necessary
to assess
whether
an activity
acts on the stimulating
or on the proliferating cell.
Liquid
cultures
of monocytes,
obtained
cells,
from
were
light-density
ny-stimulating
soft
agar
density
R
white
used to observe
factor
(CSF)
cultures
of nonadherent
bone marrow
cells were
ECENTLY
WE
human
serum
inhibiting
activity
indirectly
colony-forming
had
no effect
by
stimulating
cells.
on CSF
marrow
producing
cells and that
proliferating
cell population
a direct negative
feedback
lightused to
that
on
pro-
duction
but inhibited
the action
of CSF.
Serum-inhibiting
activity
correlated
with
the circulating
neutrophil
concentration.
These
observations
suggest
that
serum
stimulation
of granulopoiesis
is achieved
and
REPORTED
is due
effects
Medium
molecular
weight
serum-stimulating activity
increased
monocyte
CSF production
but had no effect on colony-forming cells.
High molecular
weight
serum-
on cole-
production,
R. Galbraith
determine
blood
effects
Peter
the
to a substance(s)
granulopoietic
requiring
stimulating
the
presence
CSF-
growth
of
is stabilized
loop.
the
by
activity
of
of monocytes
for
its expression.
In a large
serum
survey,
none of the normal
and only 5% of the
patient
sera examined
stimulated
growth
in cultures
of nonadherent
light-density
bone marrow
cells (NALD
BMC),
whereas
all normal
and 95% of patient
sera
stimulated
colony
growth
when
monocytes
were
included
in the cultures.
These
results
suggest
that under
normal
conditions
it is unlikely
that serum
contains
a
substance
Serum
tion.
that stimulates
granulopoiesis’
contains
inhibiting
and stimulating
Inhibiting
activity
is generally
tein,2 and stimulating
slightly
less than that
In this
study
monocyte
activity
is thought
of albumin.3
we examined
and NALD
the hypothesis
concentration
addition,
neutrophil
regarded
Culture
medium.
acids,
serum-inhibiting
vitamin
B,2,
was
(58#{176}Cfor
I 20 mm)
From
the Division
Submitted
Supported
Address
Stuart
©
304
St.,
1979
June
lOOX
used
human
Kingston.
by Grune
lipopro-
with
molecular
weight
-stimulating
colony
activity
forma-
in separate
pyruvate,
The
tissue
medium,
1% of 200
culture
In
METHODS
supplemented
mM
medium
with
L-glutamine,
was
2%
and
of lOOX
0.2%
of
with
30%
supplemented
nonessential
1000
mEq/ml
heat-treated
serum.
ofHematology,
14, 1978;
accepted
Cancer
requests
Ont.
AND
tissue culture
sodium
(Gibco).
by Ontario
reprint
weight
and
affect
BMC
cultures
to determine
their mechanisms
of action.
that serum-inhibiting
activity
is related
to the circulating
was tested.
CMRL-1066
1% of
that
molecular
to be a glycoprotein
MATERIALS
amino
activities
as a high
& Stratton,
University.
October
19, 1978.
Treatment
to Fraser
K7L
Queen’s
and
L. Baker,
Research
Ph.D..
Kingston,
Ont.
Foundation
Div.
Grant
of Hematology.
309.
Queen’s
University,
/02
2V6.
Inc. 0006-4971/79/5302-001
7$02.00/0
Blood,
Vol.
53.
No.
2 (February),
1979
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MECHANISM
OF
ACTION
OF
The colony-forming
Petri
dishes
density
or serum
blood
for
assessed
on
was
The
day
at
7 by
culture
2 ml per
then
more than
90%
monocytes,
on monocyte
CSF
humidified
tants
CSF
CSF
dishes
were
content
stored
CO2.
were
Colony
cells
as colonies,
±
I SE of triplicate
mean
light-
below).
Serum
set
up and
formation
using
was
an
inverted
counts.
Colony
cultures
in this
for
I .5-2
hr to allow
decanted.
The
over
could
were
in each
be assayed
indicates
the
number
layers,
(see
examined
of colonies
of
for effects
incubated
at
37#{176}Cin a
The
at 20%
cells.
composed
experiment.
for CSF
of
WBC
of adherent
cell
being
Cultures
LD
106
attachment
Substances
layer.
to the bottom
4 X
adherent
is indicated
they
and
of cells adhering
incubating
superna-
in NALD
that
BMC
formed
in the
assay.
BMC.
NALD
the
Bone
anticoagulant.
Pasteur
I .072)
and
separation4
the
The
cells
cells
to remove
WBC.
washed
then
drawn
from
to settle
spun
and
specified
condition
down
CSF
2 X
NALD
was
106 LD
millipore
prepared
WBC/ml
Preparation
source
the
with
heat-treated
I0
were
NALD
using
buffy
was
cut
and
were
sodium
serum
off
plasma.
a
The
(sp.
to an
to each
as
with
albumin
subjected
added
citrate
drawn
1 20 mm)
in human
recovered
BMC
coat
(58#{176}Cfor
by a single-density
cells
volunteers
gr.
adherence
culture
to provide
at 900
g for
0.3%
the
cultures
(means
(2
volunteers
into
plasma
washed
thrice
density
X
l0
±
drawn
with
separation
1 SD),
Vacutainers
was
heat-treated
cells/culture),
used
to prepare
pipette.
(58#{176}Cfor
The
to provide
sodium
a Pasteur
LC
120
WBC
± 8% monocytes,
56.3%
was
containing
off with
procedure.
± 8% lymphocytes,
43%
basophils
by conditioning
were
medium
with
ID
incubated
in 100-mm
pore
and
stored
and
-inhibiting
size),
a Sephadex
of serum-inhibiting
10 mm,
using
of serum-stimulating
with
normal
leukocyte-rich
mm)
fraction,
0.2%
0.6%
±
colony-stimulating
adherent
cell
cells
layers,
and
to
CSF.
(0.45-sm
through
Eluate
thrice
informed
for 2 hr. The
BMC
with
filtered
waseluted
(8/liter).
0. 1% ±
medium
10 mm,
I X
plasma, and depleted
of neutrophils
composed
of0.4% ± 0.6% neutrophils,
eosinophils,
g for
light-density
and
normal
informed
2000
separated
The
monocytes,
Blood,
were
was
from
at
cells.
was allowed
cells
aspirated
were
neutrophils.4
target colony-forming
citrate,
was
centrifugation
of nucleated
to remove
LD
marrow
After
pipette
suspension
for
20
either
(see
cultures
5%
by
of incubation
as “CSF”
added
Triplicate
2 ml medium.
at +4#{176}Cuntil
was
prepared
cells
with
than
liquid
1007)
included
is expressed
layer.
as the
were
nonadherent
Duration
were
(CSF)
layer in 35-mm
specified,
number.
of 2-mI
layers
overlayered
were
factor
When
containing
more
expressed
(Falcon
the
atmosphere.
the cultures
cultures.
cell
below).
in this
in colony
consisted
and
production
5% CO2
from
Petri
agitated
are
increases
0.3% agar (Difco)
I -ml
(see
atmosphere
containg
; results
adherent
60-mm
were
incorporated
aggregates
system
BMC
or colony-stimulating
with
The
of a single
NALD
were
at 40X
plates
consisted
37#{176}Cin a humidified
scoring
dishes.
305
contained
WBC)
to increase
monocyte
below) in
(LD
microscope
Petri
system
that
to be tested
observed
60-mm
The
cells
7 days
transmission
size
1008)
components
incubated
FACTORS
cell culture
(Falcon
white
SERUM
K1, between
activity.
GlOO
0.03
column
and
Eluate
Petri
WBC:
dishes
5-mi
aliquots
for 3 days.
of a suspension
The
supernatant
containing
was
decanted,
at + 4#{176}C.
Fresh normal
activities.
(diameter
50 mm,
V0 350
0.14
(containing
lipoprotein)
with
K,
0.43
between
and
ml,
was
0.54
human
V
1090
collected
(eluting
serum
with
saline
and
used
as the
immediately
CSF
1.5
0/0
serum
stimulatIng
2.5
act vity
after
stimulotson
LDWBC
Fig. 1 .
Effect
of serum-stimulating
activity
on colony
formation
in NALD
BMC cultures
stimulated
with
either
CSF
(0) or LD WBC ( 0) in the same experiment.
(25 ml)
ml)
stimulation
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BAKER
306
AND
GALBRAITH
U(I)
(-3
0
05
serum
0/0
albumin)
millipore
volume,
10
stImulating
Fig. 2.
Effect
of serum-stimulating
activity
on monocyte
CSF production.
Serum-stimulating
activity
added
to otherwise
serum-free
monocyte cultures
and incubated
for 5 days. Supernatants were
assayed
for CSF at 20 % in NALD
BMC culture.
Amount
of CSF detected
in supernatant
is indicated
by ‘CSF’
and reflects
the
number
of colonies
that
formed
in the CSF
activity
assay.
was collected and used as the source of serum-stimulating
filtered and stored at +4#{176}C.Kay was calculated
as ( V V0 the void
volume,
and
V, the
bed
activity).
V0)/(
V,
These preparations
V0), where
-
V
were
the
5
eluted
volume.
RESULTS
ofSerum-Stimulating
Effect
Activity
Colony
included
formation
in cultures
Colony
stimulated
formation
was not
by serum-stimulating
Two experiments
results.
in
NALD
of NALD
of this
BMC
BMC
Effect
design
CSF
were
completed,
cultures.
in otherwise
repeatedly,
with
each
activity
or LD
whereas
cultures
producing
comparable
Activity
in NALD
BMC
cultures.
Serum-inhibiting
formation,
regardless
of the nature
of the stimulus
(Fig.
of serum
inhibiting
activity
was observed
in five separate
independent
samples
of serum-inhibiting
activity.
activity
CSF
(I)
5,
stimulation
0
(-3
3.
Effect
formation
with either
experiment.
CSF
of serum-inhibiting
in NALD BMC cultures
(0) or ID
WBC
(0)
activity
on
stimulated
in
the
10
same
0/0
serum
inhibited
3 and 4). This
experiments
C
0
Fig.
it was
(Fig.
1).
Serum-stimulating
activity
stimulated
serum-free
monocyte
cultures
(Fig. 2).
with
several
independent
samples
of
colony
colony
was
WBC.
activity.
ofSerum-Jnhibiting
Colonyformation
Serum-stimulating
with either
affected
in CSF-stimulated
cultures,
activity
in LD WBC-stimulated
CSF production
in monocyte
CSF production
when included
This
observation
was made
serum-stimulating
cultures.
stimulated
inhibiting
activity
effect
using
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MECHANISM
OF
ACTION
OF
SERUM
307
FACTORS
701
60
50
‘I,
4)
40
C
0
0
U
Fig. 4.
Effect
of serum-inhibiting
colony formation
in NALD BMC cultures
with CSF.
activity
on
stimulated
5
0/0
0
serum
inhibiting
CSF production
in monocyte
cultures.
In this experiment,
production
by monocytes
was observed
by setting
up replicate
and withdrawing
them
neous CSF production
with
30% heat-treated
monocyte
CSF
activity
the rate of CSF
monocyte
cultures
from the incubator
at various
times,
up to 40 hr. Spontawas ensured
by using tissue
culture
medium
supplemented
human
serum.
Serum-inhibiting
activity
did not inhibit
production
(Fig.
5). This
observation
was
made
in two
additional
experiments.
Activity
ofHuman
First,
column
Serum
Fractions
5 ml of normal
fresh human
(diameter
2.5 cm., V0 40 ml,
fractions
were collected
with CSF.
Significant
Assessed
serum
V 120
fractions
and added
at 20% to cultures
inhibiting
activity
was observed
eluting
with
BMC
Cultures
was eluted
through
a Sephadex
GlOO
ml) with saline
(8 g/liter).
Then
5-ml
eluted
at 50 ml (Fig. 6). This experiment
was
stimulation;
each
time,
significant
inhibitory
serum
in NALD
repeated
activity
of NALD
BMC
stimulated
only in the fraction
that
four times using
was associated
LD WBC
only
with
lipoprotein.
30
20
“CS
Fig.
/
F”
i0
1
6
2
Duration
18
of
24
incubation
5.
Effect
of
serum-inhibiting
activity
(20 % ) on monocyte
CSF production.
Replicate
monocyte
cultures
were
set up and incubated
for various
durations.
Incubation
medium
was supplemented
with
30 % heat-treated
human serum;
in this medium
monocytes
produce
CSF spontaneously.
as indicated
30
in hours
36
40
by the open circles.
Monocyte
cultures
containing
serum-inhibiting
activity
are
indicated
by the
solid
circles.
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308
30
BAKER
AND
GALBRAITH
-
if
0
if
Bed
vcsume
Fig.
6.
fractions
colony
40
Elution
Relationship
Circulating
Between
Serum
Neutrophil
Sera,
ollected
from
whose
neutrophil
fractionated
Colony-Inhibiting
Activity
normal
subjects
concentrations
on the
and
from
were
Sephadex
Serum
circulating
Patient
intravenous
serum
Gi 00)
on
assessed
NALD
with
BMC
CSF.
at
cultures
and
“hematologically
reduced
G100
Fractions
eluting
at 45, 50, and 55 ml were
inhibiting
activity
in cultures
of NALD
BMC
experiment.
Inhibiting
activity
was observed
by
which correlated
with the circulating
neutrophil
Regulation
formation
20 % in
stimulated
(ml)
of
Concentration
patients
infection,
were
Volume
Effect
(Sephadex
normal”
by drugs
or elevated
by
column
described
above.
pooled
and assayed
at 10% for
stimulated
with CSF
in a single
all of the sera,
the magnitude
of
concentration
(Fig. 7).
of Granulopoiesis
was obtained
from
two
neutrophil
concentration:
I was
infusion
a 63-yr-old
of
female
cyclophosphamide,
Fig. 7.
Effect of circulating
neutrophil
concentration
on
serum-inhibiting
activity.
Sera.
obtained
from
patients
with
neutrophil
concentrations
between
140
and
11,200
cells I mm3, were fractionated,
and the high molecular
weight
fractions
were
assessed
at
1 0 % for activity
in NALD BMC
cultures
stimulated
with CSF.
with
patients
during
advanced
carcinoma
methotrexate,
Circuloting
drug-induced
of
and
the breast
5-fluororacil
Neutrophii
Concentration
variations
who received
on
day
(cells/mm3)
0.
in
a single
Serum
was
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MECHANISM
OF
ACTION
OF
SERUM
309
FACTORS
8600
50
#{149}5000
ID
40
-4000
Dl
Circulating
Neutrophil
-3000
30
Concentration
Colonies
(cells/mm3)
(0-0)
2000
20
io.
5000
a
0
i’O
0
Time
i’S
after
Fig. 8.
Relationship
between
on colony formation
(0) assessed
obtained
from two
patients
during
also assessed for activity in NALD
obtained
regularly
Patient
2 was
admission
hospital,
neutrophil
sera
observed
days,
at 1 0 %
during
female
her
who
fever
tested
neutrophil
fell
at
F
0
0
I
2
concentration
BMC
cultures
her
3
(0
) and
stimulated
episodes
of neutropenia.
(#{149}
Fig. BA).
which
normal
.
30
4
days
Ifl
in NALD
drug-induced
BMC culture
overshot
25
of study
circulating
concentration
were
medium
formation
When
LD
30
and
a 25-yr-old
to the
circulating
The
culture
for
recovered,
cells/mm’,
20
initiation
circulating
whole
by
Sera
neutrophil
ID
serum’s
WBC.
from
were
one patient
were
concentration
fell
severe
had
to normal.
rose
from
10%
for
960
neutropenia
We
to 5300
their
due
then
to phenylbutazone.
obtained
daily
Two
serum
with
the
effect
circulating
on
colony
neutrophil
formation.
The
after
her
tissue
Colony
with serum.
(Fig.
8A).
and was
concentration
0
0
-.78
(Fig.
8).
078
r5-
40
while
B
50
r5
530
cells/mm3.
was not supplemented
A
53.
days
samples
did not occur
in cultures
that contained
NALD
BMC
only
WBC were included
in the cultures,
colony
formation
occurred
inversely
to
values.
used in this experiment
to vary
effect
Sera
40
0
0
U)
0
4)
0
30
#{149}E30
0
0
00
0
U
8
20
0
a
0
20
0
0
io
l0
0
0
0
00
(5
.
0
Circulating
2500
neutrophI
(cells
5000
concentration
/mm3)
Fig. 9.
Relationships
between
serum’s
concentration
(A) and circulating
monocyte
stimulated
with ID WBC. See Fig. 8 and text
0
0
0
0
is,
0
.
.
250
500
Circulating
monocyte
( cells
-
750
.
000
i250
concentration
/mm3)
effect
on colony
formation
and circulating
neutrophil
concentration
(B) assessed
in NALD
BMC
culture
for description
of sera.
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310
BAKER
The correlation
concentration
was
coefficient
-0.78
varied
the
course
during
formation
and
between
(Fig. 9A).
of these
circulating
colony
formation
The circulating
studies;
monocyte
GALBRAITH
and circulating
neutrophil
monocyte
concentration
also
however,
no correlation
concentration
AND
was
between
observed
(Fig.
colony
9B).
DISCUSSION
Gra nulopoiesis
produce
regulatory
Likewise,
involves
factors,
colony
formation
actions
in which
and colony-inhibiting
Marrow
ing
factors
cell cultures
serum;
however,
indicating
that
cells
free
essentially
formation.
colony
action
also
marrow
cells
of
respond
cells
but
Blood
to added
cannot
cells
of stimulating
to assay
colony-forming
substances
determine
and
respond
for CSF
and
generally
been
used
regulating
inter-
to assay
NALD
of such
considered
cell, and liquid cultures
of monocytes
factors
on CSF production.
factors
cultures
BMC
cells
sigmoidally
to CSF.’3
Thus
and for factors
that inhibit
are
involves
(CSF
by monocytes6’7
the proliferating
cells.
have
whether
versa.
cultures
which
factors.5
to proliferate
spontaneously,9”#{176}
are present.
Thus assays
employ-
To do so requires
vice
and
leukocytes,
to these
cells
cells
influence
capacity
cells
cells.
cells,
monocytes
stimulating
of regulatory
marrow
have the
proliferating
or on stimulating
stimulating
free
spontaneously”2
can be used
by human
produced
by nonproliferating
activity
by neutrophils4’8’9)
such cultures
stimulating
and
unseparated
proliferating
interactions
between
nonproliferating
and proliferating
cells, which
respond
act
on
of proliferating
populations
do not
are
form
colonies
NALD
BMC
CSF-stimulated
cultures
colony
to be a model
can
be used
of the
marrow
to assess
the
An additional
important
consideration
of culture
systems
used
to assay
for
regulatory
factors
is that the tissue
culture
medium
serum
supplement
be free of
regulatory
activity.
Serum regulatory
factors
are thermolabile.’
Thus tissue culture
medium
appropriately
supplemented
with heat-treated
serum
provides
an environment
that
regulatory
supports
factors.
growth
and does
Such a supplement
not
was
interfere
with the action
used in this investigation.
of exogenous
serum
stimulating
-k’
4-
activity
-
S F-*
‘e-
graniocytes
W
stimulating
;
.
cell
3
Fig. 1 0.
Schematic
description
of the regulation
of granulopoiesis.
..
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MECHANISM
OF
Normally,
-inhibiting
lates
ACTION
OF
serum
activities.’
monocytic
cells (Fig.
evaluated
311
contain
CSF but does exhibit
colony-stimulating
molecular
weight
serum-stimulating
activity
production
of CSF
(Fig.
relationships
since
the
development
inhibiting
FACTORS
does not
Medium
1 ). In vivo
adequately,
technical
SERUM
to increase
activity
inhibits
2)
but
has
no effect
of serum-stimulating
monocyte
culture
its sensitivity.
colony-forming
molecular
(Figs.
3 and
on monocyte
CSF production
(Fig. 5). The magnitude
relationship
to the circulating
neutrophil
concentration
(Fig.
Whole
serum
obtained
from patients
during
drug-induced
of NALD
BMC
stimulated
with
LD
between
colony
formation
and circulating
9A). Such a relationship
is consistent
with
neutrophils
produce
serum-inhibiting
activity.
The results
of our studies
led us to the following
granulopoiesis
(Fig.
10):
The
granulopoietic
proliferating
cell populations,
the proliferating
cell population
by stimulating
cells.
The
endotoxin-stimulated
production
production.
of the
consists
in serum’
this
are brought
about
by serum
Growth
of the proliferating
stabilized
circulating
through
description
support
and
no such
bears
a
assessed
of
and
cavity.’4
Growth
of
is produced
locally
rapid
clearance
Increases
that
regulation
of stimulating
the
concept.
factor(s)
granulocyte
serum-
has
WBC,
showed
an inverse
neutrophil
concentration
the concept
that circulating
system
of CSF
CSF’6
but
of its activity
7).
neutropenia,
which
are located
in the marrow
is stimulated
by CSF,’5
which
absence
serum
not yet been
additional
weight
4)
effect
in cultures
relationship
(Figs.
8 and
on colony-forming
activity
have
system
requires
High
cells
and
stimu-
of
in granulocyte
act to enhance
local
progenitor
cell population
CSF
is
by a direct
negative
feedback
loop.
This
feedback
loop consists
of
granulocytes
that produce
serum-inhibiting
activity,
which
circulates
the marrow,
where
it acts directly
on the proliferating
cells to inhibit
their
proliferation.
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Mechanism of action of serum factors that regulate granulopoiesis in vitro:
possible physiologic role of serum-inhibiting activity
FL Baker and PR Galbraith
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