November. 1995. 585 expression on THE-i myelomonocytic cells by macrophage colony-stimulating factor in combination with interleron-y. Edward. S. Kimball,*.
Activation
of cytokine
production
and adhesion
molecule
expression on THE-i myelomonocytic cells by macrophage colony-stimulating factor in combination
with
interleron-y Edward
S. Kimball,*
*Oncology tDepartment School
Abstract:
ofMedicine,
THP-1
cultured
with
Elizabeth
and Endocrinology ofCell Biology,
Kovacs,t
Research, Neurobiology
Maywood,
leukemia
macrophage
cells
colony-stimulating
greater
have
been
This
enhanced
when
M-CSF
of
predicted cytokine
and
when M-CSF to the cells. human M-CSF.
amounts
production
IFN-ywere
blood
treated ofthe
taming M-CSF and IL- 1 and TNF-a. no effect of IFN-y
IFN-y inhibited Northern blotting alone on IL-1
production. observed
and TNF-a mRNA 6 h after treatment
1
IL-1 at 2 and
and
served
at
compared tured only augmented ments
higher
2
h after
with with
with
cytokines, in augmented .
monocytic M-CSF against
levels These
the production of studies revealed or TNF-ct mRNA expression with M-CSF
with
mRNA In addition
combinations cell surface
of IFN-yand expression
1 and vascular accompanied by that included aggregation, These phenotypic
in cytokine expression expression may be related
was
IFN-y
+
for suggest
resulting
of M-CSF
was or
expression was with IFN-y +
observed results
cytokine synthesis.
moleculeThis was
of IFN-? with fresh
expression
production
combinations
functional changes extensive homotypic like appearance. hancements molecule
mRNA
treatment
mRNA M-CSF.
cytokine
due to increased tokine protein
adhesion cute- 1
IL-1
or
with IFN-y + cultures con-
IFN-y + M-CSF. Higher TNF-a mRNA observed at 2 and 6 h after treatment M-CSF,
observed
simultaneously
h after addition were obtained
cells treatment
and Craig
R. Schneider* and University,
Stritch
and
that
Key 1
contained
Leukoc.
J.
Words:
tumor
and
58:
IFN-y
.
in combina-
585-594;
1995.
cell adhesion
interleukin-1
.
M-CSF Biol.
molecules interferon-gamma
cell
.
cytotoxicity . mRNA
. M-CSF
. ICAMTHP-1
.
. VCAM-1
necrosi.sfactor
TNF-cc than mechanisms. was
added
was added 24 Similar results
peripheral Cycloheximide
IL-13 and by additive
tures tion.
factor (M-CSF) or interferon-y (IFN-y) alone produce, at best, only low levels ofinterleukin-1 (IL-13) and tumor necrosis factor a (TNF-a). However, combinations of the two factors resulted in at least 3- to 20-fold would
Clark,*
Foundation, Spring House, Pennsylvania Burn and Schock Trauma Unit, Loyola
IllinoLc
myelomonocytic
either
M. Christina
Janssen Research and Anatomy,
ob-
M-CSF
cells cutthat the from
IFN-y
treatoccurs
and increased to up-regulating
cy-
INTRODUCTION Various
soluble
monocytic
factors
cell
subsequent
have
growth,
been
maturation,
acquisition
of properties
and bactericidal and tumoricidal vated macrophages. Macrophage (M-CSF),
also
termed
affecting
necrosis
CSF-1
{7]
secretion
factor
by mature
activation,
been
reported
motes the macrophages (MHC) (ICAM-1)
[6],
modulate
cytokine
with synthesis
[1],
is important
by actifactor
for prolifera-
marrow-derived mononuhas been reported to be tumoricidal activity [3, 4] (IL-i)
interferon-y
(IFN-y)
[5], [6],
tumor
and
IL-6
macrophages.
Monocyte also
like
of interleukin-1
(TNF)
to
differentiation,
toxicity exhibited colony-stimulating
tion and differentiation of bone clear phagocytes [2]. M-CSF capable of enhancing monocyte and
reported and
maturation, to be
and
a property
differentiation
of IFN-y,
have
which
pro-
maturation of peripheral blood monocytes to [8], induces major histocompatibility complex
class II and intercellular expression [9-1 1], amplifies
adhesion molecule 1 inflammatory cytok-
M-CSF resulted of intercellular cell adhesion morphological
moleand
plastic adherence, and a macrophagechanges and
en-
and cell surface to activation of
cells to become cytotoxic effectors by and IFN-y combinations. In vitro cytotoxicity A-375 melanoma cells was greatest for cut-
Abbreviations: nosorbent assay; antigen; adhesion
CHX, cycloheximide; ELISA, FITC, fluorescein isothiocyanate;
hPBL, human peripheral molecule 1; IFN-y,
IL-i,
interleukin-!;
LPS,
lipopolysaccharide;
MEM,
minimal
vascular
cell
Reprint Research,
LFA-i,
essential
requests: May
lymphocyte
medium; molecule Edward
Janssen
Received
blood leukocyte; interferon-y; IgGi,
M-CSF,
adhesion
Research 8,
1995;
enzyme-linked HLA, human
S.
TNF,
tumor
necrosis
very
Kimball,
Oncology
late
Spring
August
antigen
colony-stimulating
1; VLA-4, Foundation,
revised
ICAM-1, intercellular immunoglobulin Gi;
function-associated
macrophage
immuleukocyte
3,
factor; activation and
House, 1995;
1;
factor; VCAM-1, antigen
4.
Endocrinology PA
19477-0776.
accepted
August
4,
1995.
Journal
of
Leukocyte
Biology
Volume
58,
November
1995
585
me production
[8, 12],
and
promotes
TNF
over
the course
of 2 to 4 weeks
if IFN-y period.
is supplied to the Cytokine-induced
be hastened maturation
Culture Conditions
monocyte/macrophage
antimicrobial [13] and antitumor activity Human peripheral blood monocytes quire the ability to secrete constitutively [8].
This
acand
process
lEN+MCSE
can
U. 6000
z
cells throughout this macrophage activa-
I’-
E 4000
,
on monocytes [1 1, 15-18], and this has been shown to improve their in vitro antitumor effector cell properties [16, 19-21]. Numerous studies report the use of IFN-y as a agent or in combination [8, 22, 23], and others
phage
colony-stimulating
with involve
of the use of IFN-y absence of LPS, in
the
adhesion
of cytokine
production
and
6 hrs
cell
activation [23]. There are fewer reports in combination with M-CSF, but in the context
2000
lipopolysaccharide granulocyte-macro-
(GM-CSF)-induced
factor
Vehicle
0 lEN
tion, resulting in cytokine synthesis and tumoricidal activity, is now known to involve the expression of cell surface adhesion molecules. IFN-y, IL-1, and TNF-a can induce ICAM-1 and vascular cell adhesion molecule 1 (VCAM-1)
single (LPS)
.
8000
[14]. will gradually M-CSF, IL-i,
describe
leukemic IFN-yand production. man
experiments
THP-1
peripheral
blood
alone.
In vitro
target
cells
cells.
Flow
cytotoxicity
A-375
against
+ M-CSF alone.
2000
,-
-J
E
exam-
Dl
as a consequence of higher levels of ICAMafter IFN-y treatment
studies
revealed that IFN-y either single cytokine
than
studies
48 hrs
MCSF lEN IFN + MCSF
monocytic
cytometric
molecule expression treatment revealed than were obtained
24 hrs
Vehicle
cells as a model system in which combinations of M-CSF were shown to enhance IL-1 and TNF-a Similar experiments were carried out with hu-
ining adhesion IFN-y + M-CSF 1 and VCAM-1
tive
using
48
3000
molecule
expression.
We
hrs
24 hrs
0.
1000
melanoma
was
more
effec0
6 hrs
MATERIALS
AND
METHODS
Reagents Human
lL-1
kits
were
ELISA
kits
were
purchased
tissue
All
culture
pur(lsased
(strain
ci x
x 10
LPS U/tng were
i0
U/mg)
used for flow sources: CD-18, clone
W6/32
clone
antigen
Biosciences,
purchased Cambridge,
(CDS4),
(IgCl)-isotype
clone
1G11
clone
control,
IgG2a
late
IgG
la),
activa-
mouse
Isotype
anti-mouse
insmu-
control,
and
(Becton-Dicken-
CA).
Collection lin, cells
586
A-375
were
(Rockville, in RPMI
streptomycin, were
and
maintained
Journal
MD). 1640
of
obtained THP-1
medium 10%
from cells
fetal
bovine
Biology
American
tnaintained
supplemented
at subconfluent
Leukocyte
were
the
with serum
densities
Volume
Type
in
58,
Culture
x
at < 0.5
L-glutamine,
(RPM!
expression
either
production
one in
100
U/mI
medium
by TIIP-1
cells
showing
time
experiment
culture
supernatants
M-CSF,
1000
U/mI),
M-CSF cells
h,
as
U/ml
cultured course
of
a function
IFN-y,
medium). Dulbecco’s
November
106
penicilA-375 minimal
1995
(100
had
Pilot
M-CSF
of
or both.
and
100
production
when
by human
peripheral
hPBL
IL-i
manufacturer’s oritnetric
and
and
TNF-a
test
in
that
isolated
Endotoxin
levels
24,
blood
of
the
M-CSF production in 24-well diluted and THP-1
according
quantitated Walkersville,
or 1000
cytokine
penicillin, from
and
IFN-y
performed
ELISA, were
h after
6,
augmenting
heparinized
Bioproducts;
at
Cytokine
was
supernatants
and
24
recombinant
!FN-y.
L-glutamine,
After
combination
in
by commercial
(Whittaker/MA
added of either
human
in (1000
medium
sampled
M-CSF with
the
M-CSF.
was
the
(hPBLs)
with
quantitated
directions. LAL
than
leukocytes
supplemented were
M-CSF were
human
1 ml of freshly
and RPM!
For
cells/mI
106
IFN-y
concentrations
in combination blood
1640
cultures
M-CSF
of
with serum.
either
of IFN-y
cases,
effective
natural
used
containing
tomycin.
U/tnl
x
at 0.5
volume
lower
bovine
with
Supernatants
that less
from
equal
some
IFN-y.
revealed
different
RPM!
In
fetal
cultured
or a combination an
supplemented
10%
supplemented
with
considerably
IFN-y not
with
U/ml),
received
were
were
medium
refed
studies
formulation and
cells
supplements.
cells
U/ml
THP-1
were
appropriate
48 h.
high-glucose streptomycin,
or RPM!
24 the
(MEM)
penicillin, production
plates
and
cells/mi
medium
L-glutamine,
was
Cultures Tl-IP-1
essential
RPM!
WestCD1
very
(AMAC);
mouse
(FITC)-goat
with
cytokine
clone
(AMAC,
1 (LFA-1,
(AMAC);
HP2/1
(1-2
HLA-DR,
8H10
antigen
treatments
IL-!f3
from
M-
IFN-y
from the following MA); HLA-ABC,
clone
IL-iD
and Data
coli
Antibodies
IN);
and
TNF-a M-CSF.
serum,
human
human
Indianapolis,
ICAM-1
CDw49d),
Natural
International.
function-associated VCAM-1,
Jose,
Biosource
bovine
Escherichia
KS).
DIFCO.
TNF-
+
(Camarillo,
fetal
recombinant
studies were 31118 (Endogen,
n isothiocyanate
San
son,
from
(VLA-4,
Cl
fluorescei
from and
Human
International including
(Lenaxa,
activity)
purchased
Amersham.
Biosource
purchased
(AMAC); 4
noglobulin
was
cytometry clone
from
Biosciences
Biosciences);
25.3.1
tion
from
JRH
lymplmcyte
ME);
purchased components,
specific
(Harlan
(Harlan
B-Fl
brook,
were
media
from
011i:B4)
CSF
1. Enhanced !FN-y
TNF-a
a ELISA CA).
Fig. with
1:5 strepand to the
by MD)
a colthat
TABLE
The
1.
Combination
of M-CSF
and Experiment
!L-13
Vehicle
M-CSF
TNF-a 162 ±
1 2
1
3
16±8
335
±
9
41 ±
4
127±
IL-1 5±1
2
1
3 aIFNY of cultures. sensitivity samples.
19
that
!FN-y
+
(Table
±
6
7769
9 ±
0
1075
25
1115±
±
U/mI)
± 50
tion, had
no
detectable
M-CSF-treated
bacterial
supernatants
M-CSF-containing account
and
cultures.
for the
cellular
level
RNA
was
pared ized
effect and
testing. Miniinutn ± SD of triplicate
as
previously
isolated
obtained
from
from
Dr.
S.
Dr.
in
were
!FN-y
or
IFN-y
+
insufficient
to
guanidinium
et al.
cDNA
(Upjohn Sharp
Houston,
[24].
Blots for
Kalamazoo,
Dohme
+
IFN-?,
pre-
were
hybrid-
human
IL-1
MI)
Research
production numbers
TX)
were
and
during
TNF-cx
cells 1000
fluorescent for
stained
Data
and
The
were
control for 24 an
medium, All
The
antibody, and on
then
100
buffers
cells at
fixed
were
again,
1%
an
M-CSF, which
ratio
radioactivity
a Skatron
calculated perimental
from cpm
x 100. All
samples
cell -
the following spontaneous were
into system.
specific
formula: specific cptn)/(maximuin
tested
were
main-
cells
were
added
an
supernatants
The
% cptn
cells
Table
contained
!FN-y,
target
Following the
effector
which
+
A-375
of 20:1.
released harvesting
THP-1
cultures,
or M-CSF
51Cr-labeled
effector-to-target
dishes.
pJ. The
!FN-y,
rio meas-
100 with
with
LPS
560
supernatants the increased
(i.e., IL-1
after
an amount M-CSF and 2 pg/ml). and TNF-a
1
C.) 10 U U
0. U)
0 4
3
2
1
Experiment 6. Improved
Fig.
cocultured experiments
cell-mediated
THP-1
with
control
medium
performed
The
in
increased
creted
combined
TNF
may
effect
cells with
probably
have
were
acted
multiple
combinations
may
up-regulate
was
IFN-y.
The
have
tential the
use
an is
tion,
and
U/ml
cytokines
presented of THP-i
M-CSF.
IFN-y,
be
a
may in this
cells
cell-mediated
the
fashion
They
as a model
antitumor
to
StCrlabeled
or IFN-y
6.
in 7.
are
known
been
9.
murine macrophage interferon activity.).
pathways. receptors in the presecreted,
demonstrate system
to cells
as
the
po-
1 1.
12.
for evaluating
maturation molecule
13.
and acquiup-regula-
14.
cytotoxicity.
3.
Stanley,
ER.
growth
and
used
mean
as targets.
percent
Both
cytotoxicity
cells ±
were SD
from
Ia antigen
expression
(i982)
differentiation
Structure-function
studies
257, !3679. Tushinkski, RJ., Bartelmz, lineage-specific hemopoietic
ofa
colony
stimu-
C/tern.
Stimulation factor
S.H. (1983) CSFgrowth factor. J.
of macrophage tumoricidal CSF-1. Cell. Immunol. 105,
i8.
activity
ICAM-!
in
human
serum:
et al.
141,
induction
cell agents
with
immune
lines and
of
intercellular
adhesion
by pro-inflammatory cytokneutralizing antibodies. J.
1665.
Webb, D.S., Mostowski, H.S., Gerrard, hancement of ICAM-! expression results
Cytokine-induced envulnerability of tumor cells to monocyte-mediated lysis. J. Immunol. 146, 3682. Rice, G.E., Munro, J.M., Corless, C., Bevilaqua, M.P. (199!) Vascular and nonvascular expression of INCAM-ilO. A target for mononuclear leukocyte adhesion in normal and inflamed human tissues. Am. J. Pathol. 138, 385. Rice, G.E., Bevilacqua. M.P. (1989) An inducible endothelial cell surface glycoprotein
270.
Kimball
17.
by a lymphokine
Buckle, AM., Hogg, N. (1990) Human memory T cells express intercellular adhesion molecule-i which can he increased by interleukin 2 and interferongamma. Eur. J. Immunol. 20, 337. Gerrard, T.L., Siegel, J.P., Dyer, DR., Zoon, K.C. (1987) Differential effects of interferon-a and interferon-y on interleukin 1 secretion by monocytes. J. Immunol. 138, 2535. Nathan, CF., Murray, H.W., Weibe, ME., Ruhin, BY. (1983) Identification of interferon-)’ as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J. Exp. Med. 159, 8!2. Jett, JR., Montovani. A., Herberman, RB. ( !980) Augmentation of human monocyte-mediated cytolysis by interferon. Cett. Immunot. 54, 425. Rothlein, R., Mainolfi, E.A., Czajkowski, M., Marlin, S.D. (1988) A form of
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