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Histamine stimulates prostaglandin E production by rheumatoid synovial cells and human articular chondrocytes in culture.

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HISTAMINE STIMULATES PROSTAGLANDIN E
PlRODUCTION BY RHEUMATOID SYNOVIAL CELLS
AND HUMAN ARTICULAR CHONDROCYTES
IN CULTURE
DAVID J. TAYLOR, JOAN R. YOFFE, DIANE M. BROWN, and DAVID E. WOOLLEY
Histamine stimulates prostaglandin E (PGE) production by cultures of adherent rheumatoid synovial
cells and human articular chondrocytes. When subcultured synovial fibroblasts or human articular chondrocytes were “primed” by preincubation with conditioned media from primary adherent rheumatoid
synovial cell cultures (synovial factor), each produced
even higher PGE levels upon histamine exposure. This
histamine stimulation was prevented by histamine HI,
but not H2,antagonists and was more marked if serum
was absent from the culture media. Thus, histamineinduced PGE production by these cells is mediated via
HI receptor activation and subsequent arachidonic acid
liberation.
Inflamed rheumatoid synovial tissue produces
high levels of prostaglandin E (PGE), and primary
cultures of adherent cells prepared from this tissue
continue to elaborate PGE in vitro (1). Over time in
culture, the adherent rheumatoid synovial cells (ASC)
produce less PGE until, after several subcultures, the
levels are barely detectable. However, these subcultures of ASC can be stimulated to produce high levels
of PGE by a number of factors including those from
~~.
From the Department of Medicine, University Hospital of
South Manchester, Manchester, United Kingdom.
Supported by grants from the Arthritis and Rheumatism
Council. the Medical Research Council, and the North West Regional Health Authority, UK.
David J. Taylor, PhD: Research Fellow; Joan R. Yoffe,
PhD: Research Fellow; Diane M. Brown. BSc: Research Assistant;
David E . Woolley, PhD: Senior Research Fellow.
Address reprint requests to David J. Taylor, PhD, Department of Medicine, University Research Laboratories, University
Hospital of South Manchester, Manchester, M20 8LR, UK.
!Submitted for publication November 28. 1984; accepted in
revised form July 12, 1985.
Arthritis and Rheumatism, Vol. 29, No. 2 (February 1986)
blood monocytes (2), conditioned medium from cultured synovium (3), and even crystals (4). The extent
to which other inflammatory agents, such as mast cell
histamine, might contribute to PGE production by the
rheumatoid synovium has not previously been studied,
although some evidence supports its involvement. For
example, the histamine H2 receptor antagonist,
cimetidine, was shown to suppress both acute and
chronic inflammation in the rat adjuvant arthritis
model (5). Since mast cells have been observed at
cartilage erosion sites in rheumatoid joints (6), and
increased numbers of mast cells have been reported in
rheumatoid synovium (7,8), we have examined the
effects of histamine and its antagonists on PGE production by primary cultures of adherent rheumatoid
synovial cells. Moreover, since marked differences
were observed in the histamine response of rheumatoid synovial fibroblasts and human articular chondrocytes (9), we have compared the effect of histamine
on PGE production by these cells, with and without
activation by synovial factor.
MATERIALS AND METHODS
Culture techniques. Rheumatoid synovial tissue was
obtained upon remedial synovectomy of the knees of patients with classic rheumatoid arthritis, and was dissociated
enzymatically, as previously described ( 2 ) . Adherent synovial cell cultures were established in plastic wells, measuring
23 mm in diameter (12 wells/plate; Costar, Cambridge, MA),
in Dulbecco’s modified Eagle’s medium (DMEM; Gibco
Europe, Ltd., Paisley, U K ) supplemented with 10%
(volume/volume) fetal calf serum (FCS; Northumbria
Biologicals, Ltd., Cramlington, UK), containing penicillin,
streptomycin, and fungizone. Primary cultures of ASC represented a mixed population, classified morphologically as
fibroblastic, dendritic, and macrophagic cells ( 2 ) that were
161
HISTAMINE-STIMULATED PGE
used for experiments when the cells had formed a confluent
monolayer-usually
within 7 days. Subcultured synovial
cells with predominantly fibroblastic morphology were
established by conventional trypsin treatment of primary
cultures and replating at reduced density. Articular chondrocytes were obtained by proteolytic digestion of macroscopically normal articular cartilage from femoral heads and
condyles obtained from remedial surgery, as described previously (9). The chondrocytes were cultured in the same way
as that described for the synovial cells, but using DMEM
supplemented with 15% FCS. All cultures were maintained
at 37°C in a water-saturated atmosphere of 5% (v/v) COz in
air, and when confluent, were subcultured using established
techniques (2).
F o r the experiments, confluent monolayers of adherent synovial cells o r articular chondrocytes were incubated
at 37°C in DMEM-10% FCS, with and without histamine.
Culture medium was collected after 24 hours and stored at
-20°C until assayed for PGE. Chlorpheniramine and
mepyramine were used as histamine H I receptor antagonists, and cimetidine and ranitidine were used as H 2 antagonists. Because basal prostaglandin production in subcultured synovial fibroblasts and articular chondrocytes was
generally very low and at the limits of assay sensitivity, it
proved difficult to assess whether the histamine antagonists
had a direct effect on P G E production. This was overcome
by preincubating the cells for 24 hours with 20% (v/v)
synovial factor (SF), which increased prostaglandin production, as described previously (3). The SF was prepared by
culturing primary ASC in DMEM-10% FCS, and after
centrifugation to remove cellular debris, the conditioned
medium was used without further treatment. After removal
of the SF preincubation medium the “activated” chondrocytes o r synoviocytes were washed 3 times with Hanks’
balanced salt solution before adding DMEM-10% FCS with
or without histamine, its antagonists, and on some occasions, indomethacin. This second incubation continued for
either 1 or 24 hours, except during a time course study, when
samples were removed at 5, 15, 30, and 60 minutes.
To investigate the effect of histamine on the intracellular cyclic AMP (CAMP) content of chondrocytes and
synoviocytes, the cells were incubated in DMEM containing
800 p M isobutyl-L-methylxanthine for 5 minutes at 37°C.
After removal of the incubation medium, the cells were
precipitated with boiling water, scraped from the well, and
homogenized in a ground-glass homogenizer. The homogenate was centrifuged at 1,500g for 5 minutes, and the
supernatant was retained for cAMP estimation, while the
pellet was dissolved in 0.1M NaOH and assayed for protein,
as described previously (10).
Assays. Prostaglandin E was measured in culture
media by radioimmunoassay (1 1) utilizing an antiserum
(Miles Laboratories, Ltd., Slough, UK) with similar specificity toward prostaglandins E l and E2 and using activated
charcoal (Sigma, Poole, UK) with Dextran T-70 (Pharmacia
GB, Ltd., Hounslow, UK) to separate bound fractions from
free fractions (12). The standard used in the assays was
PGE2; thus, the PGE values (PGE, + PGEz) obtained for the
samples are in terms of equivalent amounts of PGEz.
Cyclic AMP was measured using the protein binder
isolated from bovine adrenal glands (13) and (8-3H) cAMP
(Amersham International, Amersham, UK), as recently described (9).
RESULTS
Primary cultures of adherent rheumatoid
synovial cells produced substantial amounts of PGE
which was increased 2-4-fold by exposure to 1-100
Table 1. Effect of an H , antagonist on histamine-induced prostaglandin E (PGE) production in a primary culture of adherent
rheumatoid synovial cells*
I
I
0 7
I
~~
6
5
4
-log [Histamine concn.(Ml]
Figure 1. Histamine stimulation of prostaglandin E (PGE) production in a primary culture of adherent rheumatoid synovial cells.
Points represent 24-hour PGE production for cells in Dulbecco’s
modified Eagle’s medium-10% fetal calf serum, with and without
added histamine. Each point is the mean ? SEM (n = 5).
Treatment
DMEM-10% FCS (control)
Chlorpheniramine (0.6 kkf)
Histamine (4.5 kkf)
+ chlorpheniramine (0.6 w M )
* Values are mean
PGE (ngiml)
54.10 ? 0.98
60.05 t 3.71
86.19 1.27t
62.35 2 3.78
*
2 SEM of 24-hour cultures (n = 4). DMEM
Dulbecco’s modified Eagle’s medium; FCS = fetal calf serum.
t P <: 0.0005 (Student’s r-test).
=
TAYLOR ET AL
162
Table 2. Effect of H , and Hz antagonists on histamine-induced
prostaglandin E (PGE) production by a primary culture of human
articular chondrocytes*
Treatment
PGE (ngiml)
DMEM-10% FCS (control)
Chlorpheniramine (1.3 pM)
Ranitidine (31.4
Histamine (17.8 pM)
+ chlorpheniramine ( I .3 pM)
+ ranitidine (3 1.4 &f)
~
~
~~
* Values are mean or mean
<0.69
<0.55
<0.55
1.77 2 0.12
C0.71
1.77 C 0.09
~~~~
~
+- SEM of 24-hour cultures (n = 4).
DMEM = Dulbecco’s modified Eagle’s medium: FCS = fetal calf
serum.
pM histamine (Figure 1). The histamine stimulatiop of
PGE production by ASC was prevented by the H1
antagonist chlorpheniramine (Table 1). Similarly, in
primary cultures of human articular chondrocytes
(HAC), histamine stimulated PGE production, which
was prevented by chlorpheniramine, but was not preventeld by ranitidine (Table 2).
Histamine also increased PGE production by
subcultured synovial fibroblasts and HAC, especially
the 1al.ter (Table 3). When these subcultured cells were
preincubated with 20% SF, a large increase in PGE
production was observed; this was subsequently augmented by histamine exposure (Table 4). Indeed, the
histamine exposure approximately doubled the PGE
response of the SF-activated cells. The effect of histamine HI and H2 antagonists on this histamine stim4ulation of PGE production was analyzed by applying
Tukey’s test to the analysis of variance from 3 rheumatoid synovial fibroblast and 4 chondrocyte experiments. This confirmed that histamine stimulation
in bol h the fibroblasts and chondrocytes was prevented by the H1 antagonists, chlorpheniramine or
mepyramine, but not by the H2 antagonists, ranitidine
or cimetidine, although the latter had a small inhibitory
effect on chondrocytes. The analysis also showed that
mepyramine caused a small decrease in fibroblast PGE
Table 3. Effect of histamine on prostaglandin E (PGE) production
in subcultured rheumatoid synovial fibroblasts and articular
chondrocytes*
PGE (ng/ml)
Treatment
Fibroblasts
Chondrocytes
DMEM--IO% FCS (control)
Histamine (17.8 &f)
<0.25
0.74 2 0.08
0.82 t 0.08
5.37 ? 0.33t
* Values, are mean
2 SEM of 24-hour cultures (n = 4). DMEM
Dulbecco’s modified Eagle’s medium; FCS = fetal calf serum.
t P < 0.0005 (Student’s r-test).
=
production compared with that of controls, but this
was not confirmed in later experiments (data not
shown).
Figure 2 shows the time course of histamine
stimulation of PGE production by rheumatoid synovial
fibroblasts and articular chondrocytes previously “activated” by preincubation with SF. In both cell types,
marked stimulation of PGE production occurred
within 5 minutes of adding histamine; this was largely
prevented by the H I antagonist, mepyramine. The
inclusion of indomethacin (14 pki) reduced PGE production to <9% of the contrpl values, confirming that
PGE obtained during the second incubation represented new synthesis and not leakage of preformed
material. The requirement of FCS in the culture medium during these relatively short incubation periods
was investigated. When FCS was omitted from the
medium after preincubation with SF, the amount of
PGE produced in 60 minutes by articular chondrocytes
and synoviocytes was very much reduced (Figure 3).
However, the effect of histamine on PGE production
by these cells was more marked when FCS was absent
from the incubation medium (Figure 3). The stimulation of PGE production in serum-free cultures was also
prevented by mepyramine, but not by cimetidine (data
not shown), as previously observed when culturing in
the presence of FCS.
Histamine acting via H2 receptors has previously been shown to produce a severalfold increase in
Table 4. Effect of H , and H2 antagonists on histamine-induced
prostaglandin E (PGE) production by synovial factor (SF)-activated
subcultured rheumatoid synovial fibroblasts and human articular
chondroc ytes*
PGE (nglml)
Treatment
Fibroblasts
Chondrocytes
DMEM-10% FCS (control)
Chlorpheniramine (1.3 CUM)
Mepyramine (1.3 CUM)
Ranitidine (32
Cimetidine (40 CLM)
Histamine (17.8 CUM)
+ chlorpheniramine (1.3 WM)
+ mepyramine (1.3 pl4)
+ ranitidine (32 r-.M)
+ cimetigine (40 CLM,
9.67 5 0.43
8.93 t 0.35
7.09 5 0.32
7.55 C 0.44
9.04 t 0.47
17.61 t 0.90
10.34 t 0.57
10.70 2 0.76
18.51 t_ 0.86
18.86 ? 0.68
11.65 t 0.41
11.53 t 0.71
12.00 t 0.40
11.28 t 0.43
11.96 C 0.62
23.49 t 1.04
14.76 t_ 0.85
13.05 2 0.56
20.44 2 0.92
21.97 t 0.55
* Values are mean +- SEM of 24-hour cultures following the addition
of histamine and its antagonists to cells preincubated for 24 hours
with 20% SF. Values are from 3 experiments on 2 different fibroblast
preparations (n = 8-12) and 4 experiments on 4 different chondrocyte preparations (n = 12-16). Means which differed by more than
1.42 for the chondrocytes and by more than 2.25 for the fibroblasts
had a significance of P < 0.05 (Tukey test). DMEM = Dulbecco’s
modified Eagle’s medium; FCS = fetal calf seTum.
163
HISTAMINE-STIMULATED PGE
c?
E
/
.-,
v
Y
C
0
...
-a
0
YI
t
5
15
60
30
Time (minutes)
5
15
30
60
Time (minutes)
Figure 2. Time course of histamine stimulation of prostaglandin E (PGE) production by subcultured rheumatoid synovial fibroblasts (a) and
articular chondrocytes (b). Points represent PGE production after the addition of 17.8 p M histamine (O), 17.8 pLM histamine + 1.3 p M
mepyramine (W), or Dulbecco’s modified Eagle’s medium-IO% fetal calf serum (0)
to cells which had been preincubated with 20% synovial
factor for 24 hours. Each point is the mean rt SEM (n = 4). Error bars are omitted when SEM was less than the size of the symbol. A significant
increase over that of the control was detectable at 5 minutes, P < 0.001 by Student’s r-test (*).
14r
DMEM
HlST
DMEM
FCS
HIST
DMEM
HlST
DMEM
FCS
HlST
Figure 3. Effect of fetal calf serum (FCS) on histamine (HIST)stimulated prostaglandin E (PGE) production by subcultured rheumatoid synovial fibroblasts (a) and articular chondrocytes (b).
Values represent PGE production 1 hour after the addition of 17.8
p M histamine either in Dulbecco’s modified Eagle’s medium
or in DMEM-10% FCS (!3)to cells which had been
(DMEM) (0)
preincubated with 20% synovial factor for 24 hours. Values are
mean t SEM (n = 3). Histamine-increased PGE production had a
significance of P < 0.05 (*) compared with DMEM-FCS control and
P < 0.0005 (**) compared with DMEM control, by Student’s t-test.
intracellular cAMP in articular chondrocytes but only
a marginal increase in rheumatoid synovial fibroblasts
(9). ’This cAMP increase is not a consequence of the
histamine stimulation of chondrocyte PGE production, since it is observed in the presence of 14 p M
indomethacin (data not shown) and is inhibited by
histamine H2 antagonists (9).
The effect of activating chondrocyte cultures by
preincubation with SF was also found to elevate the
cAMP levels. Subsequent histamine exposure resulted
in a 3-4-fold increase in the cAMP content of the
activated chondrocytes, but this was not as pronounced as the effect of histamine on nonactivated,
control cells (Table 5). Thus, chondrocytes exposed to
histamine respond with elevated cAMP production
mediated by H2 surface receptors, and increased
prostaglandin production mediated by H I receptors.
Although histamine had little effect on intracellular
cAMP levels of subcultured synovial fibroblasts (data
not shown), it still increased PGE production via
histamine H I receptor stimulation.
DISCUSSION
Histamine has been shown to stimulate PGE
production in both primary and passaged cultures of
TAYLOR ET AL
Table 5. Effect of histamine on the cyclic AMP (CAMP)content of
articular chondrocytes, with and without previous activation by
synovial factor
Treatment*
Preincubated with DMEM-10% FCS
DMEM-IBMX (control)
Histamine (44.5 pLM)
Preincubated with 20% SF
DMEM-IBMX (control)
Histamine (44.5 ~ L L M )
Intracellular cAMP
(pmoledmg protein)t
62.79 5 1.64
529.95 2 17.36
108.71 5 15.03
382.60 2 17.59
* DMEM = Dulbecco’s modified Eagle’s medium; FCS = fetal calf
serum: IBMX = isobutyl-L-methylxanthine;SF = synovial factor.
t Values are mean ? S E M intracellular cAMP measured 5 minutes
after the addition of DMEM-IBMX o r histamine t o preincubated
chondrocytes (n = 3).
adherent rheumatoid synovial cells and human articular chondrocytes. Both cell types were activated to
produce increased amounts of PGE by exposure to
synovial factor, and histamine subsequently augmented this response by doubling PGE production.
We found that histamine stimulation was mediated via
histamine H I receptors since both mepyramine and
chloqpheniramine prevented the increase in PGE production, whereas the H2 antagonists, cimetidine and
ranititdine, had no effect on the synovial fibroblasts and
had only a slight inhibitory effect on the chondrocytes.
Although PGE release from inflamed synovial
tissue is an important factor in the pathophysiology of
the rheumatoid joint, we have an incomplete understanding of the various stimuli which promote prostanoid synthesis. Several factors have been found to
increase PGE production by subcultured adherent
synovial cells, including mononuclear cell factor (2),
the crystals sodium urate and calcium pyrophosphate
dihydrate (4), and phorbol myristate acetate (14).
Since rheumatoid synovial cells and chondrocytes in
vivo probably produce prostaglandins in response to a
variety of factors, it seemed reasonable to use synovial
factor as a tool with which to prime or activate the cells
prior 1.0 studying the effect of histamine on prostanoid
synthesis. Such an approach provided easily measurable PGE values which allowed a more detailed study of
the mechanism of histamine stimulation.
The histamine concentrations used in the
present experiments were reported to increase PGE
production from cultured human endothelial cells in a
dose-related manner ( I 5). Moreover, endothelial cell
stimulation also appeared to be mediated by HI receptor aclivation ( 1 3 , whereas bradykinin, another vasoactive agent, was reported to increase PGE production
by both endothelial (16) and fibroblast cultures (17).
The response to histamine by the activated chondrocytes and synovial fibroblasts was rapid, with
significant stimulation of PGE production detectable in
5 minutes; a similar response was reported for the
effect of bradykinin-induced prostaglandin production
by fibroblasts and endothelial cells (16,17).
Information on the mechanism by which histamine stimulates chondrocyte and synoviocyte PGE
production was provided by the effect of excluding
FCS from the culture media. The reduced histamine
effect on cells in serum-containing media would be
explained if histamine increased PGE production by
liberating arachidonic acid-the substrate for prostaglandin synthesis. In the presence of FCS, the arachidonic acid generated by histamine will be largely
masked by that in the serum. Culturing the cells in
arachidonic acid (1 pg/ml)-containing medium had the
same effect as FCS, producing increased basal PGE
production but reduced histamine effect (data not
shown). A similar observation was reported for the
effect of bradykinin on endothelial cells cultured in
medium containing arachidonic acid (16), and it has
since been shown that the bradykinin stimulation of
fibroblast PG production involves arachidonic acid
liberation (17).
The similarity between the synovial fibroblasts
and chondrocytes in terms of their prostaglandin response to histamine is in marked contrast to their
intracellular cAMP response to histamine, which is an
H2 receptor-mediated process. In articular chondrocyte cultures derived from human, canine, and
bovine cartilage, histamine directly produced a 6 1 0 fold increase in intracellular CAMP, whereas in rheumatoid synovial fibroblasts, an increase was barely
detectable (9).
Evidence is accumulating which suggests that
mast cells could play an important role in the
pathophysiology of the rheumatoid joint (7-9). The
observation of mast cells at sites of cartilage erosion
(6), the presence of histamine in rheumatoid synovial
fluids (18), and the finding that mast cell heparin
stimulates mononuclear cell factor production from
monocyte-macrophages (19) all suggest that the mast
cell could contribute to and perpetuate prostaglandin
production in the rheumatoid joint. The data presented
here indicate that histamine not only stimulates
prostaglandin production by chondrocytes and synovial fibroblasts, but can amplify and exacerbate the
PGE response of these cells previously activated by
HISTAMINE-STIMULATED PGE
synovial factor. At present, prostaglandin production
in the rheumatoid joint is inhibited by nonsteroidal
antiinflammatory drugs, but because of the requirement for prostaglandin synthesis in many physiologic
situations, this can lead to serious side effects. Consequently, the recognition and identification of the factors which regulate prostaglandin production in the
rheumatoid joint might, we hope, provide a more
specific target for t h e therapeutic management of
inflammatory joint disease.
ACKNOWLEDGMENTS
We thank Drs. H. Bertfield, H. 0. Williams, and
M. A. Morris, Consultant Orthopaedic Surgeons, for the
supply of specimens, K. A. Hale and M. Williamson for
preparation of the manuscript, and E. B. Faragher for help
with the statistical analysis.
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