Bioscience Reports, Vol. 12, No. 4, 1992
On the Signal Transducing Mechanisms
Involved in the Synergistic Interaction
Between Interleukin-1 and Bradykinin on
Prostaglandin Biosynthesis in Human
Gingival Fibroblasts
U l f H . Lerner, 1 G u s t a f Brunius, 2 and T h o m a s M o d e e r 2
Received April 6, 1992
Recombinant human interleukin-l~ (IL-lfl) and bradykinin (BK) synergistically stimulate prostaglandin E2 (PGE2) formation in human gingival fibroblasts cultured for 24 h. Neither BK or IL-1/3 per se,
nor their combinations, caused any acute stimulation of cellular cyclic AMP accumulation. BK, but
not IL-lfl, caused a rapid, transient rise of intracellular Ca 2+ concentration ([Ca2+]i), as assessed by
recordings of fura-2 fluorescence in monolayers of prelabelled gingival fibroblasts. IL-lfl did not
change the effect of BK on [Ca2+]i. Ionomycin and A 23187, two calcium ionophores, synergistically
potentiated the stimulatory effect of IL-lfl on PGE 2 formation. Three different phorbol esters known
to activate protein kinase C also synergistically potentiated the action of IL-lfl on PGEa formation.
Exogenously added arachidonic acid significantly enhanced the basal formation of PGEe. In IL-1/3
treated cells, the enhancement of PGE 2 formation seen after addition of arachidonic acid, was
synergistically upregulated by IL-lfl. These data show that i) the synergistic interaction between IL-lfl
and BK on PGE2 formation is not due to an effect linked to an upregulation of cyclic AMP or [Ca2+]6
ii) the signal transducing mechanism by which BK interacts with IL-lfl, however, may be linked to a
BK induced stimulation of [Ca2+]~ and/or protein kinase C; iii) the mechanism involved in the action
of IL-1/~ may, at least partly, be due to enhancement of the biosynthesis of prostanoids mediated by
an upregulation of cyclooxygenase activity.
KEY WORDS: Interleukin-1; -bradykinin; cyclic AMP; intracellular calcium; protein kinase C.
INTRODUCTION
I n t e r l e u k i n - 1 ( I L - 1 ) is a f a m i l y o f c l o s e l y r e l a t e d p o l y p e p t i d e s t h a t c a n b e
p r o d u c e d b y a v a r i e t y of d i f f e r e n t cells, i n c l u d i n g m a c r o p h a g e s , a n d w h i c h
possess a w i d e s p e c t r u m o f b i o l o g i c a l activities (rev. in refs. 1, 2). C o n s i d e r a b l e
1Department of Oral Cell Biology, University of UmeS, 5-901 97, Ume~, Sweden.
2 Department of Pedodontics, Karolinska Institute, Stockholm, Sweden.
To whom correspondence should be addressed.
263
0144-8463/92/0800-0263506.50/09 1992 Plenum Publishing Corporation
Lerner, Brunius and Mode6r
interest has focused on the role of IL-1 in inflammatory and immunological
reactions. The ability of IL-la~ and IL-1/3 to stimulate prostanoid biosynthesis in
several cell types of different origins has been demonstrated by many laboratories
and is regarded as one of the inflammatory properties of this pleiotropic cytokine.
Bradykinin (BK) is a nine amino acid peptide formed in inflammatory
reactions from high molecular weight kininogen due to the action of plasma
kallikrein (rev. in refs. 3, 4). This nonapeptide, which is one of the classical
proinflammatory mediators, is most well known for its effects on vessel dilatation,
vessel permeability and pain (rev. in ref. 5). Recently, evidence has accumulated
showing that functional BK receptors can be demonstrated not only on
endothelial and nerve cells, but also on other cells including fibroblasts (6),
oesteoblasts (7), macrophages (8) and smooth muscle cells (9). Many of the
actions of BK in these cells are paralleled by a stimulatory effect on prostanoid
biosynthesis.
In human gingival fibroblasts, we have demonstrated that BK, via B2receptor mediated pathway, stimulates arachidonic acid release and subsequent
prostanoid formation (6). Recently, we reported that simultaneous challenge of
the gingival fibroblasts with IL-1 and BK results in a strong synergistic interaction
on PGE2 formation (10). We also have made similar observations in neonatal
mouse calvarial bone (11). The mechanism, however, involved in the interaction
between the two peptides is not known. In the present communication, we have
studied thepossible importance of cyclic AMP, intracellular Ca 2+ ([Ca2+]i) and
protein kinase C, three signal transducing systems which have been implicated in
some of the actions of both IL-1 and BK (12-18). In addition, we have studied
whether involvement of IL-1 mediated upregulation of cyclooxygenase activity
may be involved in the synergistic interaction between IL-1 and BK.
MATERIALS A N D METHODS
Materials
Ionomycin, A 23187, arachidonic acid, bradykinin, phorbol 12,13-dibutyrate,
12-0-tetradecanoylphorbol-13-acetate, 4-/3-phorboi-didecanoate, 4-o~-phorboldidecanoate, 13-phorbolacetate and isoprenaline were purchased from Sigma
Technical Co., St. Louis, MO, USA; forskolin and fura-2 acetoxymethylester
from Calbiochem-Behring Corp., Diagnostics, La Jolla, CA, USA; c~modifcation of Minimum Essential Medium and fetal calf serum from Gibco,
Renfrewshire, Scotland and Flow Laboratories, Irvine, Scotland; recombinant
human interleukin-1/3 from Genzyme Corporation, Boston, MA, USA or from
Boehringer-Mannheim, Mannheim, Germany and the radioimmunoassay kits for
PGE2 and cyclic AMP from Du Pont/NEN, Dreieich, Germany.
Fibroblast Cultures
Cultures of fibroblasts were established from gingival biopsies obtained from
two different patients (N-17, N-21) as previously described (19). The cells were
Interactions Between IL-1 and Bradykinin
265
cultured in the 0~-modification of Minimum Essential Medium (o~-MEM) containing antibiotics and 10% fetal calf serum (FCS). Cells from passages 8-15 were
used. The cells were characterized as fibroblasts based upon morphological
criteria.
Determination of PGE2 Formation
Cells were seeded in 2 cm2 multiwell plastic dishes and grown in the presence
of 10% FCS to approximately 70% confluency. Then the cell layers were rinsed,
preincubated in serum free o~-MEM and subsequently incubated in medium
containing 1% FCS with or without test substances, as previously described (6).
The cultures were incubated for 24 h at 37~ At the end of the incubation, the
amounts of PGE2 produced was assessed by analysis of the concentration of
PGE2 in culture media using a commercially available radioimmunoassay kit and
following the instructions supplied by the manufacturer. Cells were counted using
a haemocytometer.
Measurements of Cyclic AMP Formation
Fibroblasts were seeded in 2 cm 2 multiwell plastic dishes and grown to 80%
confluency in the presence of 10% FCS. Then the cell layers were extensively
rinsed and preincubated in a water bath at 37~ in serum free, Hepes-buffered
ac-MEM containing the phosphodiesterase inhibitor rolipram (0.1 mM final
concentration). After 30 min., test substances or vehicle were added. 10 min.
later, the media were quickly withdrawn and cellular cyclic AMP extracted with
90% n-propanol at 4~ for 24 h. The extracts were evaporated and reconstituted
in assay buffer. Cyclic AMP was then analyzed by using a commercially available
radioimmunoassay kit and following the instructions supplied by the manufacturer. Cells were counted in parallel wells using a haemocytometer.
Measurements of
[Ca2+]i
Fibroblasts were prepared as described above, seeded onto coverslips and
cultured overnight in oc-MEM with 5% FCS. After loading with 1/~M fura-2
acetoxymethyl ester (AM) for 30 min., the coverslips were rinsed in a Hepes
buffer, pH 7.4, containing 1 mg/ml albumin and 1.28 mM Ca 2+ and with C1- as
the sole anion. Thereafter, the coverslips were fixed in a specially built holder and
placed in a cuvette with 1.5 ml buffer at a 30~ angle towards the excitation light
beam, in a Perkin Elmer LS-5 spectrofluorometer. [Ca2+]i was monitored by
switching the excitation wavelengths between 340 and 380 nm and recording the
emitted light at 510 nm. After subtraction of autofluorescence, the 340/380 nm
ratio for each sample was calculated. Measurements were performed at 37~ with
constant stirring using a magnetic bar (for further details see ref. 20).
Statistics
Student's two-tailed t test was used in the statistical analysis.
Lerner, Brunius and Mode6r
2(~i
Table 1.
Effects of interleukin-1/~ and bradykinin and their combinations on cyclic A M P
formation and PGEz biosynthesis in human gingival fibroblasts, In addition, the effects of
forskolin and isoprenaline are shown
Additions
Amount
-IL-1/3
-25 U / m l
50 U / m l
l #M
25 U / m l
50 U / m l
10/~M
100/~M
BK + IL-1/~
Forskolin
Isoprenaline
PGE2 ~
(pg/103 cells)
0.6
2.7
9.3
3.1
17.8
27.1
3.3
2.6
+ 0.07
+ 0.4
5:1.4
5:0.7
+ 2.5
:t:3.8
5:0.1
5:0.3
cAMP b
(pmol/10 s
cells)
2.4 5:0.6
4.7 • t . 0
3.4 5:0.8
4.4 + 1.3
1.5 5:0.5
3.1:1:0.5
247 5:75
684 + 76
Values are m e a n s • SEM for 3 - 4 wells.
a The concentration of P G E 2 was analyzed in culture media after 24 hr of treatment. Cells
from patient N-21 were used.
b Cellular content of c A M P was quantified after 10 min. of exposure to the different
agonists. Cells from patient N-17 were used.
RESULTS
In agreement with previous findings (10), we here show that both recombinant human IL-1/3 (25 and 50 U/m1) and BK (1/~M) significantly enhance PGEe
formation in 24 h cultures of human gingival fibroblasts and that simultaneous
treatment results in a synergistic interaction (Table 1). Neither IL-1/3 or BK, nor
their combinations, enhanced cellular content of cyclic AMP (Table 1). By
contrast, forskolin (10/~M) and isoprenaline (100/~M) caused a substantial, acute
increase of cyclic AMP accumulation (Table 1). Both forskolin and isoprenaline
stimulated the formation of PGE2 in 24 h cultures of human gingival fibroblasts
(Table 1).
Also in agreement with recent findings (21,22), we here demonstrate that BK
(1/~M) caused a rapid, transient increase in the level of [Ca2+]i in human gingival
fibroblasts (Fig. 1). In contrast, IL-1/3 (25 U/ml) did not affect the level of
340/380 nm
10.0
5.0
Jk
1.0
B K,10-6 M
1rain
l
IL-1 25U/m[
BKl(36M
+1[-1 25U/m[
Fig. 1. The effect of bradykinin, interleukin-1/~ and their combinations on [CaZ+]i ,
expressed as the ratio 340/380, in monolayers of human gingival fibroblasts
prelabeled with fura-2.
267
Interactions Between IL-1 and Bradykinin
Table 2. Effect of interleukin-I/3, in the absence and presence of the calcium ionophores
ionomycin and A23187, on PGEz biosynthesis in human gingival fibroblasts
Ionophores
-Ionomycin
A23187
Amount
(/tM)
-1
1
3
PGE2(pg/103 cells)
-IL-1/3
+IL-1/3 ~
2.0 ~ 0.6
16.5 • 2.80
14.0 :t: 0.9 b
100 zl: 9.1 b
4,2
290
117
293
•
•
•
+
0.40
25 c
15c
16c
Values are means • SEM for four wells. Cells from patient N-21 were used.
IL-1/3 was added to a final concentration of 25 U / m l .
0 Significantly different from untreated control (P < 0.01).
c Significantly different from IL 1/3 alone (P < 0.01),
[Ca~+]i. Nor did simultaneous addition of IL-1/3 and BK, or pretreatment with
IL-1/~, change the stimulatory response to BK (Fig. 1). The data shown in Fig. 1
are tracings obtained in experiments using cells from patient N-21 and IL-1/3 at
one concentration. Similar data were obtained also using cells from patient N-17
and by using IL-1/3 at a wide range of concentrations (0.5-50 U/ml; data not
shown).
The calcium ionophores ionomycin (1/~M) and A 23187 (1 and 3 #M) caused
a significant stimulation of PGEz formation in human gingival fibroblasts (Table
2). The effect of A 23187 was dose-related. When IL-lfl (25 U/ml) and ionomycin
were added together, a strong synergistic interaction on PGE2 biosynthesis in 24 h
cultures was obtained (Table 2). Similarly, simultaneous treatment with IL-1/3
and A 23187 resulted in a synergistic stimulation of PGE2 formation (Table 2).
Phorbol 12,13-dibutyrate (PDBu; 0.1/~M), 12-0-tetradecanoylphorbol-13acetate (TPA; 0.1/tM) and 4-/3-phorbol-didecanoate (4-fl-PDD; 0.1 #M), three
tumour promoting phorbol esters known to activate protein kinase C (23), caused
a significant stimulation of PGE2 formation (Table 3). In contrast, 4-0~-phorboldidecanoate (4-o~-PDD; 0.1/~M) and 13-phorbolacetate (0.1/~M), two phorbol
esters which do not activate protein kinase C, did not stimulate PGE2
biosynthesis. Simultaneous addition of PDBu and IL-1/3 resulted in a strong
synergistic interaction in 24 h cultures (Table 3). Similarly, TPA and 4-/3-PDD,
Table 3.
Effect of interleukin-1/3, in the absence and presence of different phorbol esters,
on P G E 2 biosynthesis in human gingival fibroblasts
Phorbol esters
-PDBU
TPA
4-/3-PDD
4-o~-PDD
13-phorbolacetate
Amount
(~M)
-0.1
0.1
0.1
0.1
0.1
PGE2(pg/103 cells)
-IL-1/3
+IL-1/3 a
1.1 :t: 0.1
12.6 9 0.4 b
11.1 • 1.1 b
12.8 + 0.6 u
0.7 + 0.1
0.6:1:0.1
13.5 + 0.7 b
794 + 59 c
505:1:55 c
688 • 37 c
12.5 + 2.2
20.2 :t: 5.9
Values are means + SEM for four wells. Cells from patient N-21 were used.
IL-1/3 was added to a final concentration of 25 U/ml.
b Significantly different form untreated control (P < 0.01).
Lerner, Brunius and Mode6r
268
Table 4. Effect of arachidonic acid, in the absence and presence of interleukin-13, on
PGE2 formation in human gingival fibroblasts
Addition
-Arachidonic acid
Amount
(p M)
-2
10
20
PGE2(pg/103 cells)
- I L-1/3
+ I L-1/3~'
0.9•
2.9 5_0.4~'
20 + 3.2b
45 -I- 6 . 3 b
1,5 5- 0.1 b
30 5- 2.3~
492 • 49c
678 5- 55~
Values are means 5- SEM for four wells. Cells from patient N-21 were used.
IL-1/3 was added to a final concentration of 25 U/ml.
b Significantly different from untreated control (P < 0.01).
c Significantly different from IL-1/3 alone (P < 0.01).
but not 4-0c-PDD and 13-phorbolacetate, synergistically potentiated the stimulatory action of IL-1/3.
Exogenous addition of arachidonic acid (2-20 # M ) to 2 4 h cultures of
gingival fibroblasts resulted in a dose-dependent e n h a n c e m e n t of PGE2 formation
(Table 4). Simultaneous addition of IL-1/3 (25 U / m l ) and arachidonic acid
(2-20/~M) for 24 h resulted in a strong synergistic, dose-dependent stimulation of
PGE2 biosynthesis (Table 4).
DISCUSSION
T r e a t m e n t of h u m a n gingival fibroblasts with IL-lfi (or IL-lo~) and B K
results in a synergistic stimulation of prostanoid biosynthesis (10). The mechanism by which IL-1 and B K interacts is not known but the interaction on
prostanoid biosynthesis is not associated with a concomitant interaction on
arachidonic acid release (although both IL-1 and B K stimulate the release of
arachidonic acid in gingival fibroblasts; 10). Since IL-1, in some cells, has been
shown to enhance cyclic A M P formation (18) and since we have observed that
agonists raising cyclic A M P can stimulate prostaglandin biosynthesis in gingival
fibroblasts (Lerner unpublished data and present study), we have explored the
possibility that this intracellular mediator was involved. Our data, however, show
that the synergistic interaction between IL-lfl and B K on PGE2 formation is not
directly correlated to a similar interaction on cyclic A M P .
In our next series of experiments, we analyzed whether the interaction
between IL-1 and B K was associated with any interaction on [Ca2+]~. In
agreement with previous observations made in a variety of B K responsive cells
including h u m a n gingival fibroblasts (21,22), we found that B K caused a rapid,
transient increase of [Ca2+]~. In contrast, IL-lfi did not affect the level of [Caa+]~.
Furthermore, neither simultaneous addition, nor p r e t r e a t m e n t with IL-1/3, did
affect the B K induced rise of [Ca2+]i. These observations show that there is no
correlation between the synergistic interaction of IL-lfi and B K on PGE2
formation and the level of [Ca2+]i.
Interactions Between IL-1 and Bradykinin
269
The rapid, transient increase of [Ca2+]i in response to BK indicates that the
rise of [Ca2+]i may be secondary to a stimulation of inositol-l,4,5-triphosphate
(IP3) formation (24). This view is supported by reports showing that BK
stimulates phosphatidylinositol 4,5-bisphosphate breakdown with subsequent
formation of inositol phosphates and diacylglycerol (rev. in ref. 4). We recently
have suggested that IP3 induced rise of [Ca2+]i and diacylglycerol mediated
activation of protein kinase C is coupled to BK induced prostanoid formation
(25). Using two different calcium ionophores, A 23 187 and ionomycin, we here
show that a rise of [Ca2+]i synergistically potentiates the IL-lfi induced
stimulation of PGE2 formation. We also show, by using different phorbol esters
stimulating protein kinase C, that activation of this enzyme leads to a synergistic
potentiation of IL-lfi induced PGE2 biosynthesis. A similar synergistic interaction
between IL-1 and protein kinase C stimulators on PGE2 formation has recently
also been observed in chondrocytes, synovial cells and human dermal fibroblasts
(26-28). Our findings suggest that both BK induced rise of [Ca2+]i and activation
of protein kinase C may synergistically interact with the mechanism by which
IL-1/3 stimulates prostaglandin biosynthesis in human gingival fibroblasts.
We previously have reported that the synergism between IL-lfi and BK on
prostanoid biosynthesis is not associated with a synergistic interaction on
arachidonic acid release, suggesting that the level of interaction is distal to
phospholipase A2 (10). In agreement with this view, we here report that
simultaneous addition of arachidonic acid and IL-1/3 also results in a synergistic
interaction on PGE2 formation. This finding suggests that IL-1/3 has the capacity
to upregulate the metabolism of arachidonic acid, a view further supported by
reports showing that IL-lfi can stimulate the biosynthesis of cyclooxygenase at
the transcriptional level in human dermal fibroblasts (28,29).
In summary, our observations indicate that the synergistic interaction
between IL-lfi and BK on prostanoid formation may be linked to BK induced
rise of [Ca2+]i and activation of protein kinase C as well as to IL-lfi induced
upregulation of cyclooxygenase activity.
ACKNOWLEDGEMENTS
This investigation was supported by grants from the Swedish Medical
Research Council (projects No. 7211 and 7525), the Swedish Association Against
Rheumatic Diseases, the Royal 80 Year Fund of King Gustav V, and by
Astra-Hfissle AB. The authors gratefully acknowledge the skilful technical
assistance of Mrs Birgit Andertun and Mrs Inger Lundgren.
REFERENCES
1. Dinarello, C. A. (1989) Interleukin-1 and its biologically related cytokines. Adv. lmmunol.
44:153-205.
2~ di Giovine, F. S. and Duff, G. W. (1990) Interleukin 1: the first interleukin. Immunology Today
11:13-18.
270
Lerner, Brunius and Mode6r
3. Proud, D. and Kaplan, A. P. (1988) Kinin formation: mechanisms and role in inflammatory and
diabetic diseases. Ann. Rev. lmmunoL 6:49-83.
4. Lerner, U. H. (1992) Effects of kinins, thrombin and neuropeptides on bone. In: Cytokines and
Bone Metabolism (Gowen, M., ed). CRC Press, pp. 267--299.
5. Marceau, F., Lussier, D., Regoli, D. and Giroud, J. P. (1983) Pharmacology of kinins: their
relevance to tissue injury.and inflammation. Gen. Pharmacol. 14: 209-229.
6. Mod6er, T., Ljunggren, O. and Lerner, U. H. (1990) Bradykinin-2 receptor-mediated release of
[3H]arachidonic acid and formation of prostaglandin E2 in human gingival fibroblasts. J. Per. Res.
25: 358-363.
7. Ljunggren, 6., Vavrek, R., Stewart, J. M. and Lerner, U. H. (199!) Bradykinin induced burst of
prostaglandin formation in osteoblasts is mediated via B2 bradykinin receptors. J. Bone Min. Res.
6:807-815.
8. Lerner, U. H., Sahlberg, K. and Ljunggren, O. (1989) Thrombin and bradykinin enhance
prostaglandin production in human peripheral blood monocytes. J. Oral Pathol. Med. 18:246250.
9. Regoli, D. and Barab6, J. (1980) Pharmacology of bradykinin and related kinins. Pharmacol.
Rev. 32:1-46.
10. Lerner, U. H. and Mod6er, T. (1991) Bradykinin B1 and B2 receptor agonists synergistically
potentiate interleukin-l-induced prostaglandin biosynthesis in human gingival fibroblasts.
Inflammation 15: 427-436.
11. Lerner, U. H. (1991) Bradykinin synergistically potentiates interleukin-1 induced bone resorption
and prostanoid biosynthesis in neonatal mouse calvarial bones. Biochem. Biophys. Res. Cornmun.
175: 775-783.
12. Shirakawa, F., Yamashita, U., Chedid, M. and Mizel, S. B. (1988) Cyclic AMP--an intracellular
second messenger for interleukin 1. Proc. Natl. Acad. Sci. USA 85:8201-8205.
13. Zhang, Y., Liu, J.-X., Yip, Y. K. and Vilcek, J. (1988) Enhancement of cAMP levels and of
protein kinase activity by tumor necrosis factor and interleukin 1 in human fibroblasts: Role in the
induction of interleukin 6. Proc. Natl. Acad. Sci. USA 85:6802-6805.
14. Bouchelouche, P. N., Reimert, C. and Bendtzen, K. (1988) Effects of natural and recombinant
interleukin-lo~ and -/3 on cytosolic free calcium in human and routine fibroblasts. Leukemia
2: 691-696.
15. Corkey, B. E., Geschwind, J.-F., Deeney, J. T., Hale, D. E., Douglas, S. D. and Klipatrick, L.
(1991) Ca2+ responses to interleukin 1 and tumor necrosis factor in cultured human skin
fibroblasts. Possible implications for Reye syndrome. J. Clin. Invest. 87:778,786.
16. Rosoff, P. M., Savage, N. and Dinarello, C. A. (1988) Interleukin-1 stimulates diacylglycerol
production in T lymphocytes by a novel mechanism. Cell 54:73-81.
17. Munoz, E., Beutner, U., Zubiaga, A. and Huber, B. T. (1990) IL-1 activates two separate signal
transduction pathways in T helper type II cells. J. Immunol. 144:964-969.
18. Mizel, S. B. (1990) Cyclic AMP and interleukin 1 signal transduction. Immunology Today
11: 390-391.
19. Mod6er, T., Dahll6f, G. and Otteskog, P. (1982) The effect of phenytoin metabolite p-HPPH on
the proliferation of gingival fibroblasts in vitro. Acta Odont. Scan& 40:353-357.
20. Arkhammar, P., Nilsson, T. and Berggren, P.-O. (1989) Glucose-stimulated elllux of Fura-2 in
pancreatic/3-cells is prevented by probenecid. Biochem. Biophys. Res. Commun. 159:223-228.
21. Lerner, U. H:, Brunius, G., Andur6n, I., Berggren, P.-O., Juntti-Berggren, L. and Mod6er, T.
(1992) Bradykinin induces a B2 receptor mediated calcium signal linked to prostanoid formation
in human gingival fibroblasts in vitro. Agents and Actions. (in press).
22. Boyajian, C. L., Garritsen, A. and Cooper, D. M. F. (1991) Bradykinin stimulates Ca2+
mobilization in NCB-20 cells leading to direct inhibition of adenylatecyclase, A novel mechanism
for inhibition of cAMP-production. J. Biol. Chem. 266:4995-5003.
23. Nishizuka, Y. (1988) The molecular heterogeneity of protein kinase C and its implications for
cellular regulation. Nature 334: 661-665.
24. Berridge, M. J. and Irvine, R. F. (1989) Inositol phosphates and cell signalling. Nature
341:197-205.
25. Ljunggren, O., Fredholm, B. B., Nordstedt, C., Ljunghall, S. and Lerner, U. H. (1992)
Involvement of protein kinase C in bradykinin-induced prostaglandin formation in osteoblasts.
(Manuscript in preparation. )
26. Arner, E. C. and Pratta, M. A . (1991) Modulation of interleukin-l-induced alterations in
cartilage proteoglycan metabolism by activation of protein kinase C. Arthr. Rheum. 34:10061013.
27. Taylor, D. J., Evans, J. M. and Wooley, D. E. (1988) Comparative effects of interleukin-I and a
Interactions Between IL-1 and Bradykinin
271
phorbol ester on rheumatoid synovial cell fructose 2,6-biphosphate content and prostaglandin E2
production. Biochem. Biophys. Res. Commun. 150:349-354, 1988.
28. Raz, A., Wyche, A. and Needleman, P. (1989) Temporal and pharmacological division of
fibroblast cyclooxygenase expression into transcriptional and translational phases. Proc. Natl.
Acad. Sci. USA 86:1657-1661.
29. Raz, A., Wyche, A., Siegel, N. and Needleman, P. (1988) Regulation of fibroblast cycloxygenase
synthesis by interleukin-1. J. Biol. Chem. 263: 3022-3028.