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Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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However, recent reports have suggested that the activities of the different COX isozymes, constitutive COX-1 and inducible COX-2, may be associated with different eicosanoids end products. For example, it was demonstrated in rat peritoneal cells that COX-2 activity favored PGE2 or prostacyclin production, whereas COX-1 activity favored TXA2 production (7, 8). To explain these findings, the authors suggested compartmentalization or functional linkage of COX isozymes with the different terminal synthases (7) or the induction of PGE synthase in conjunction with COX-2 (8, 9).
Confirming these observations, we observed in the present study that in the presence of COX-1 alone, TXA2 was produced in excess of PGE2, whereas after the induction of COX-2 the eicosanoid ratio was reversed. However, these conditions involve substantial differences in availability of PGH2. Therefore, we examined to what extent differences in the kinetic properties of the terminal synthases may explain the differences in the ratios of PGE2 and TXA2, which had been attributed to the respective COX isozymes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Materials were obtained from the following sources: AA and
carboxyheptyl-imidazole (CI) (Sapphire Bioscience, Sydney, Australia);
NS-398, rabbit PGE2 anti-serum, and COX-1 and
-2 Abs (Cayman Chemical, Ann Arbor, MI); PGH2
(Calbiochem-Novabiochem, La Jolla, CA); TXA2,
thromboxane B2 (TXB2)
antiserum prepared from a rabbit immunized with thromboxane conjugated
to human thyroglobulin as used in previous studies (10);
pyrogen-free Lymphoprep (Nycomed, Oslo, Norway); E-Toxa-Clean, LPS,
zymosan, DTT, and glutathione (Sigma, St. Louis, MO);
{5-(4-pyridyl)-6 (4-fluorophenyl)-2,3-dihydroimidazo (2, 1-b)
thiazole} (SKF86002) (Calbiochem, San Diego, CA);
1
,25-dihydroxyvitamin D3 (Biomol, Plymouth
Meeting, PA); Trans-blot transfer membranes (Bio-Rad, North Ryde,
Australia); and peroxidase-labeled donkey anti-rabbit Abs and
enhanced chemiluminescence Western blotting analysis system (Amersham,
Little Chalfont, England). Serum-treated zymosan (STZ) was prepared by
boiling zymosan for 1 h and then incubating it with freshly
prepared human serum for 24 h before washing and resuspension
in PBS.
Monocyte isolation
Buffy coats were obtained from the Red Cross Blood Center (Adelaide, South Australia). Mononuclear cells were separated by centrifugation (800 x g, 30 min) on pyrogen-free Lymphoprep. Monocytes were then isolated by countercurrent centrifugal elutriation (JE-5B Elutriation System; Beckman, Palo Alto, CA). Purity of monocytes was confirmed at >85% by FACS analysis, and contaminant cells were nearly all lymphocytes. All glassware was washed with E-Toxa-Clean to minimize LPS contamination.
U937 cells
Cells were cultured in RPMI 1640 supplemented with 10% FCS and penicillin/gentamicin.
Experimental procedure
Elutriated monocytes or U937 cells were resuspended at 2 x
106 cells/ml in RPMI 1640 supplemented with
low-LPS 10% FCS and penicillin/gentamicin. Monocytes were stimulated
with LPS (20 ng/ml final concentration) overnight in nonadherent teflon
Minisorp tubes (Nunc, Copenhagen, Denmark) in a total incubation volume
of 1 ml at 37°C with 5% CO2. U937 cells were
incubated overnight with 1,25-dihydroxyvitamin
D3 (9.8 x
10-9 M) to promote
monocytoid differentiation and then were stimulated with STZ (100 ng/ml
final concentration) overnight or for the indicated times. After the
incubation periods, cells were washed two times in RPMI and then
resuspended in RPMI (no FCS) at 2 x 106
cells/ml. AA was added and cells were incubated at 37°C with 5%
CO2 for 4 min, which was in the linear range of
eicosanoid production (data not shown). AA was diluted and stored in
ethanol at –20°C. PGH2 was stored in ethanol
at –70°C. Ethanol did not exceed 0.1% in experiments. The
incubations were terminated by snap-freezing the cell suspension in
ethanol/dry-ice bath. When pharmacologic agents were added, cells were
preincubated with the agent for 5 min before the experiment, with the
exception of SKF86002, which was incubated overnight during cell
stimulation.
Disrupted cell preparations
Methods were adapted from those described previously (11, 12). U937 cells were resuspended at 10 x 106 cells/ml of Tris-base buffer (0.1 M Tris, 1 mM glutathione, and 0.5 mM DTT) and then sonicated twice at 4 W for 1 min using a probe sonicator. The sonicate was centrifuged, and the cell debris pellet was discarded. PGH2 was added and sonicate was incubated at 37°C with 5% CO2 for 4 min.
Western immunoblot
Cell pellets (5 x 106) were resuspended in lysis buffer (HEPES-buffered HBSS (pH 7.4), 0.5% Triton X-100, 10 µg/ml PMSF, 10 µg/ml leupeptin, and 10 µg/ml aprotinin) and sample buffer (0.125 M Trizma base (pH 6.8), 20% glycerol, 4% SDS, and 10% 2-ME). The samples were then boiled for 5 min and loaded onto 12% acrylamide gel. Proteins were transferred at 4°C for 16 h at 300 mA current onto a Trans-blot membrane. The membranes were then soaked for 30 min at 25°C in TBS (25 mM Tris-HCl (pH 7.6), 0.2 M NaCl, and 0.15% Tween 20) containing 5% dried milk (weight to volume ratio) and then were exposed to anti-COX-1 or -COX-2. The membranes were then washed twice with TBS and incubated with HRP-conjugated donkey anti-rabbit Ab. Bound Abs were revealed with the enhanced chemiluminescence reagent following the manufacturer’s protocol (Amersham).
PGE2 and TXA2 measurements
Cell suspensions were stored at -20°C. Cell suspensions were
centrifuged, and supernatants were used for eicosanoid measurements.
TXA2 has a half-life of 
30 s under
physiological conditions and is converted to the stable metabolite
TXB2. PGE2 and
TXB2 levels were determined by RIA.
Statistical analysis
Analyses were performed using a two-tailed Student’s t test. Significance as indicated on graphs represents p values <0.01.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Freshly prepared human monocytes were prepared from peripheral
blood by elutriation. In these cells, eicosanoid production increased
in response to the addition of increasing concentrations of exogenous
AA (Fig. 1
a). At the lower end
of the range of AA concentrations, TXA2 was
produced in excess of PGE2. With a high
concentration of AA, PGE2 was produced in excess
of TXA2. The concentrations of AA at which the
half-maximal rate of PGE2 and
TXA2 production occurred were 8 µM and 0.4
µM AA, respectively. The maximum rate of production for
PGE2 (18 ng/2 x 106
cells/4 min) exceeded that of TXA2 (10 ng/2
x 106 cells/4 min).
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). After cells were treated with LPS,
the pattern of eicosanoid production in response to changing AA
concentrations remained similar to that in resting cells (Fig. 1
b). The concentrations of AA at which half-maximal rates of
PGE2 and TXA2 production
occurred were 8 µM and 0.3 µM AA, respectively. The maximum rate
of production of PGE2 in response to the AA was
greater in the LPS-treated cells (38 ng/2 x
106 cells/4 min) than in resting cells (see
above). In contrast, the maximum rate of TXA2
production was similar in resting and LPS-treated cells (10 ng/2
x 106 cells/4 min).
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Eicosanoid production in the human monocytic cell line U937 was
similar to that seen in elutriated human monocytes (Fig. 3a). With concentrations up to
3 µM AA, TXA2 synthesis exceeded that of
PGE2. However, from 5 to 25 µM AA, there was no
further change in the rate of TXA2 synthesis,
whereas PGE2 levels increased substantially.
Above 25 µM AA, there was no significant increase in either
eicosanoid.
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Effects of exogenous AA on eicosanoid production in STZ-treated U937 cells
COX-2 was induced when U937 cells were treated with STZ (Fig. 4). Under these conditions, there was
greater production of both PGE2 and
TXA2 in response to exogenous AA compared with
unstimulated cells (Fig. 3b). The maximum rates of
production of PGE2 and TXA2
synthesis in STZ-treated cells were 29 and 9 ng/2 x
106 cells/4 min, respectively, i.e.,
approximately double the values for resting cells. By contrast, the
concentrations of AA-producing half-maximal rates of eicosanoid
production were similar to those in resting cells, namely, 10.5 µM AA
for PGE2 and 0.7 µM AA for
TXA2.
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Effects of TXA synthase inhibition
U937 cells were preincubated with the TXA synthase inhibitor CI
for 5 min before the addition of increasing concentrations of exogenous
AA. There was >85% inhibition of TXA2 synthesis
and an increase in PGE2 synthesis at all
concentrations of AA in resting (Fig. 5a) and STZ-treated (Fig. 5b) cells.
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Exogenous PGH2 was added in increasing
concentrations to sonicated U937 cell preparations as described in
Materials and Methods. At concentrations of
PGH2 of 10 µM or less,
TXA2 synthesis exceeded that of
PGE2 synthesis (Fig. 6). At higher concentrations,
PGE2 was the predominant eicosanoid produced. The
Kms (Michaelis constant) for PGE and for TXA synthase were 17 and 1
µM PGH2, respectively.
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Aspirin, an irreversible COX inhibitor, was used at two doses to
reduce PGH2 production incrementally. U937 cells
were preincubated for 5 min with aspirin before the addition of AA. At
all concentrations of AA, aspirin inhibited PGE2
synthesis to a greater extent than TXA2 synthesis
(Fig. 7). There was a dose-dependent
inhibition of PGE2 synthesis by aspirin, and this
was seen at essentially all concentrations of exogenous AA examined. By
contrast, aspirin had no effect on TXA2 synthesis
at the lower dose and only a modest inhibitory effect at the higher
dose of aspirin. Similar results were seen in STZ-treated cells in
which COX-2 was induced (Fig. 7), except that no significant inhibition
of TXA2 production was seen even at the higher
dose of aspirin.
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The p38 mitogen-activated protein kinase inhibitor SKF86002 is an
inhibitor of COX-2 induction (13). At all concentrations
of exogenous AA, 10 and 100 nM SKF86002 inhibited
PGE2 synthesis, whereas
TXA2 synthesis was unaffected (Fig. 8).
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To assess production of PGE2 and
TXA2 at different stages of COX-2 induction,
supernatants were assayed at several time points after STZ addition
(Fig. 9). TXA2 was
detectable after 1 h and was seen in increasing amounts at
subsequent times. By contrast, PGE2 was not
detectable until 4 h. Both SKF86002 (an inhibitor of COX-2
induction) and NS-398 (a selective COX-2 inhibitor) inhibited
PGE2 synthesis more completely than
TXA2.
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). In the
absence of CI, the initial accumulation in TXA2
exceeded that of PGE2 synthesis. In the presence
of CI, TXA2 production was minimal and was
exceeded by PGE2 throughout. The quantity of
PGE2 produced in the presence of CI was
approximately equal to the aggregate amounts of
PGE2 and TXA2 produced in
the absence of CI.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The issue of proportionate production of PGE2 and
TXA2 has been addressed only recently using rat
peritoneal exudate cells. In these cells, both endogenous AA (liberated
by A23187) and a single dose of exogenous AA led to synthesis of
TXA2 in excess over PGE2.
However, when the cells were treated with LPS or TNF- to induce
COX-2, there was an alteration in eicosanoid ratios to an excess of
PGE2 over TXA2 production
(7, 8, 9). To explain these results, it was suggested that
COX-1 and COX-2 are functionally coupled to different terminal synthase
enzymes (8, 9) or that the results were because of
different intracellular distributions of COX-1 and COX-2 and different
intracellular locations of the terminal synthases (7).
This notion has been referred to previously as compartmentalization
(15, 16). This explanation for the differential regulation
of PGE2 and TXA2 remains
speculative and does not take into account other possibilities arising
from the enzyme kinetics of the terminal synthases.
Because both PGE synthase and TXA synthase can be expected to have
distinctive kinetic properties and because these properties will
influence the ratio of PGE2 and
TXA2 produced under conditions of differing
AA/PGH2 availability, we undertook to determine
their response to changing substrate concentrations in human monocytic
cells. The patterns of eicosanoid synthesis in response to increasing
AA concentrations in fresh human monocytes were similar to those in the
human monocytic-cell line U937, which had been treated with
1,25-dihydroxyvitamin D3 to induce monocytoid
maturation (17, 18). The major difference between fresh
human monocytes and the U937 cells was the increase in maximum velocity
for TXA synthase after cell stimulus seen in the latter. This is in
accord with the effects of 1,25-dihydroxyvitamin
D3, which is a known inducer of TXA synthase
(19).
In resting U937 cells, we detected only COX-1, whereas in STZ-treated cells, COX-2 was also detected. In the presence of COX-1 or COX-2, there were three distinct ranges of exogenous AA based on the profile of the eicosanoids produced.
First, with the addition of <5 µM AA, TXA2 was produced in greater amount than PGE2, suggesting that TXA synthase has a higher rate constant than PGE synthase. Second, from 5 to 25 µM AA, there was an increase in PGE2 synthesis, whereas TXA2 synthesis was unchanged. The increasing amount of PGE2 in this range of AA indicates that COX was not saturated with AA and that COX-1 and -2 were not rate limiting for PGE2 production. However, the plateau in TXA2 production suggests that the TXA synthase had become saturated. Third, with the addition of >25 µM AA, there was a plateau in PGE2 synthesis, suggesting that either COX or PGE synthase had become saturated. Overall, these findings establish PGH2 concentration and the kinetic properties of TXA and PGE synthase as crucial determinants of the ratio of PGE2/TXA2 synthesis. Furthermore, these parameters apply with or without COX-2 induction, suggesting that the kinetic properties of the terminal synthases are sufficient to determine the PGE2/TXA2 ratios.
To determine whether the lack of increase for PGE2 production in response to >25 µM exogenous AA was due to COX or PGE synthase saturation, experiments using the TXA synthase inhibitor CI (20) were performed. In the presence of a constant amount of AA, TXA synthase inhibition is expected to increase the availability of PGH2 for PGE synthase (by preventing PGH2 catalyzis to TXA2). If PGE synthase was saturated by >25 µM AA, there should be no further increase in PGE2 production with CI present. However, we observed an increase in PGE2 production at >25 µM AA in the presence of CI, indicating that PGE synthase was not saturated. This was seen in both resting and STZ-treated cells, i.e., in the presence of both COX-1 and -2. These results suggest that COX-1 and -2 become rate limiting before providing enough PGH2 to saturate PGE synthase.
Although the interpretation of the results of experiments utilizing exogenous AA is limited in its application to that with endogenous AA, the results regarding relative eicosanoid production in both circumstances were similar. With cell stimulation, endogenous AA is mobilized from membrane phospholipids for the production of eicosanoids (21). The production of PGE2 characteristically is detectable from 2 to 6 h after stimulation (9, 15, 22), the time at which COX-2 up-regulation is detectable (23). Importantly, we have shown that TXA2 was produced significantly earlier than PGE2. This has been observed in fresh, nonadherent human monocytes (G.E.C., unpublished data); adherent human monocytes (24); and murine macrophages (25) as well as in animal models of inflammation (26). As was the case with exogenous AA, this finding also supports the proposal that TXA synthase, compared with PGE synthase, has a greater affinity for PGH2, whether the latter is synthesised from endogenous or exogenous AA. Additionally, we demonstrated that after STZ exposure, the time of onset of PGE2 production from endogenous AA could be shortened from 4 h to 1 h by the addition of the TXA synthase inhibitor CI. Thus, the important factor involved in PGE2 production from endogenous AA appears to be the availability of PGH2 rather than presence of the COX-2 isozyme.
To examine more directly the influence of PGH2, exogenous PGH2 was used to compare the kinetic parameters of the terminal synthases. The Km and maximum velocity values for PGE synthase were greater than those for TXA synthase. This order was similar to the relativities of the apparent kinetic parameters for the terminal synthases estimated by the use of exogenous AA. The values are similar to those previously reported in disparate cell systems. (12, 27, 28, 29).
The observed kinetic differences in PGE synthase and TXA synthase predict differential effects on PGE2 and TXA2 synthesis by COX inhibition. Aspirin, an irreversible inhibitor of COX (30), was used to inhibit eicosanoid production in response to exogenous AA in resting and STZ-treated cells. Aspirin was chosen over other nonsteroidal anti-inflammatory drugs (NSAID) because increasing AA concentrations cannot reverse the COX inhibition. Because aspirin has a lower ID50 for COX-1 than for COX–2 (31), higher concentrations were used to inhibit COX-2. It was observed that in both unstimulated cells (expressing COX-1 alone) or stimulated cells (expressing predominantly COX-2), PGE2 production was much more sensitive to inhibition by aspirin than TXA2. The differential inhibition of eicosanoid production by aspirin thus favors synthesis of TXA2 relative to PGE2 in the presence of COX-1 or COX-2.
The family of p38 mitogen-activated protein kinase inhibitors, of which
SKF86002 is a prototypic member, inhibits mononuclear cell IL-1ß and
TNF- production. Members of this class are currently under
development for clinical applications. We have shown previously that
SKF86002 inhibits COX-2 induction in elutriated human monocytes
(13). Cell suspensions were incubated overnight with LPS
in the presence of increasing concentrations of SKF86002 to inhibit
COX-2 induction incrementally. For cells that were then washed and
treated with exogenous AA, PGE2 production was
inhibited by SKF86002 in a dose-dependent manner, whereas
TXA2 synthesis was unaffected.
When the production of PGE2 and TXA2 was followed in STZ-treated cells in the presence of either SKF86002 or the selective COX-2 inhibitor NS-398, it was found that both PGE2 and TXA2 synthesis were inhibited but that the inhibition was greater for PGE2. Thus, PGE2 synthesis was shown to be more influenced by strategies that reduced availability of PGH2 (derived from endogenous AA) than was TXA2 synthesis.
In summary, an NSAID, a selective COX-2 inhibitor and an inhibitor of COX-2 induction, preferentially decreased PGE2 compared with TXA2 synthesis. This was the case whether PGH2 was formed from exogenous or endogenous AA or whether it was synthesized by COX-1 or COX-2.
The clinical implications of these findings may be important,
particularly with regard to use of NSAID and selective COX-2
inhibitors, because a shift in the
PGE2/TXA2 balance in favor
of TXA2 may increase synthesis of the
inflammatory cytokines IL-1ß and TNF- (6). Thus, the
short-term effects of these agents on the pain and swelling of
inflammation and arthritis may be achieved at the cost of an increased
propensity to long-term tissue damage with which these cytokines have
been associated.
With regard to the mechanisms of regulation of PGE2 and TXA2 production by monocytes, our data show that the extent of PGH2 generation coupled with the respective kinetic properties of PGE and TXA synthase are important determinants of the ratio of PGE2/TXA2 produced.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Peter S. Penglis, Rheumatology Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA, Australia.
3 Abbreviations used in this paper: PGE2, prostaglandin E2; TXA2, thromboxane A2; AA, arachidonic acid; COX, cyclooxygenase; PGH2, prostaglandin H2; CI, carboxyheptyl-imidazole; TXB2, thromboxane B2; STZ, serum-treated zymosan; NSAID, nonsteroidal anti-inflammatory drug.
Received for publication January 5, 2000. Accepted for publication May 17, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1ß synthesis by thromboxane A2 in nonadherent human monocytes. J. Immunol. 158:351.[Abstract]
, and IL-6 in the human monocytic cell line U937. Immunology 79:229.[Medline]
,25-dihydroxyvitamin D-3. Biochim. Biophys. Acta 877:423.[Medline]
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