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Department of Experimental Pathology, St. Bartholomew’s and The Royal London School of Medicine and Dentistry, London, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(PPAR) can prolong inflammation in response to
leukotriene B4. Although cyclooxygenase 2 has been
shown to be induced by PPAR activation, the effect of PPAR agonists on
the key inflammatory enzyme systems of nitric oxide synthase (NOS) and
stress proteins has not been investigated. The effect on these of
naturally occurring eicosanoid PPAR agonists (leukotriene
B4 and
8(S)-hydroxyeicosatetraenoic acid, which are
PPAR selective; PGA2, PGD2,
PGJ2, and 
12PGJ2, which are
PPAR
selective) and the synthetic PPAR agonist Wy14,643 was
examined in activated RAW264.7 murine macrophages. Leukotriene
B4 and
8(S)-hydroxyeicosatetraenoic acid stimulated
nitrite accumulation, indicative of enhanced NOS activity.
PGA2, PGD2, PGJ2,
12PGJ2, and Wy14,643 reduced nitrite
accumulation, with 12PGJ2 being the most
effective. The mechanism behind this reduction was examined using
Western blotting. Inhibition of nitrite accumulation was associated
with a fall in inducible NOS protein and an induction of heme oxygenase
1, correlating both dose dependently and temporally. Other proteins
examined (cyclooxygenase 2, heme oxygenase 2, heat shock protein 70,
and glucose-regulated protein 78) were unaffected. The data suggest
that naturally occurring PPAR agonists can inhibit the inducible NOS
enzyme pathway. This inhibition may be mediated by modulation of the
stress protein, heme oxygenase 1. Thus, the generation of eicosanoid
breakdown products during inflammation may contribute to its eventual
resolution by activation of the PPAR system. This system may thus
represent a novel target for therapeutic intervention in inflammatory
disease. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One subclass of PGs, the cyclopentenone PGs, has been shown to cause a
variety of biologic effects, including cessation of cell growth (5) and
induction of cell differentiation (6). This has implications for a
variety of diseases, such as tumorigenesis and defects in lipid
physiology. In the latter field, it has been demonstrated that the
cyclopentenone PGs are among the endogenous activators of a class of
nuclear receptors, the peroxisome proliferator-activated receptors
(PPARs; for a review, see Refs. 7 and 8). These were originally
discovered from work with early hypolipidemic drugs such as the
fibrates. Ligands for these receptors include a variety of other drugs
such as the antidiabetic thiazolidinediones, xenobiotics, certain
members of the eicosanoid pathways such as the leukotrienes (LT), and
fatty acids. Three subtypes have been described to date, PPAR,
PPARß (also related to PPAR
, murine fatty acid-activated receptor,
and NUC1) and PPAR. Their activation leads to the induction of a
variety of genes such as those coding for the enzymes for ß- and
-oxidation of fatty acids (9), transferrin (10), and transthyretin
(11). In addition to this information, it is known that cyclopentenone
PGs are capable of modifying the stress response by activation of heat
shock factor 1 (HSF-1 (5)) and induction of HSP70 (12) and HO-1 (13),
which have been implicated in the biologic actions of this class of
PGs. Whether this is mediated via the PPARs is at present unclear, but
it has been demonstrated that PPARs are associated with HSP72 (14), and
it has been hypothesized that this association may be important in the
signaling pathways of these receptors.
Recently, it has been demonstrated that the inflammatory response
to leukotriene B4 (LTB4) is prolonged in
genetically modified mice with homozygous knock-out of PPAR (15).
Devchand et al. (15) proposed that, in wild-type mice, LTB4
would activate PPAR, induce fatty acid oxidation pathways, which in
turn would degrade lipid mediators of inflammation, and concluded that
activators of PPAR should be anti-inflammatory. However,
this enhanced degradation of lipid mediators has not been demonstrated
in this model, and a variety of other inflammatory mechanisms such as
those suggested above may also be important in the effects attributable
to PPAR activation.
To date, the effect of cyclopentenone PGs and other PPAR agonists on
iNOS in macrophages, a key cell and enzyme system in inflammation and
other pathologies, has not been described. In this study, we
demonstrate that 12PGJ2, a PPAR agonist,
is a potent inhibitor of iNOS activity and protein expression in
stimulated RAW264.7 macrophages. Protein expression and inhibitor
studies implicate activation of HO-1 in this phenomenon.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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RAW264.7 macrophages (European Collection of Animal Cell
Cultures) were cultured as described previously (16). Cells were
passaged and grown to 90% confluence in 96-well plates (Greiner) for
analysis of nitrite production and viability or in
75-cm2 culture flasks (Greiner, Stonehouse, U.K.) for
Western blot analysis of protein expression. Macrophages were
stimulated for 18 h (unless otherwise indicated) by addition of
100 U/ml murine rIFN- (Sigma Chemical, Poole, U.K.) and 0.1 µg/ml
LPS (LPS, Escherichia coli serotype 0111:B4; Sigma
Chemical). Concurrently administered PPAR agonist compounds were
dissolved in methyl acetate such that the final concentration of
solvent in medium was 0.1% by volume, with solvent alone as control.
At this concentration, the solvent has no effect on cellular functions
examined in this study (data not shown). Eicosanoids were purchased
from Biomol (Plymouth Meeting, PA), and Wy14,643 was purchased from
Caymen Chemical (Ann Arbor, MI). Zinc deuteroprotoporphyrin (ZnDPP;
Porphyrin Products, Logan, UT) was initially dissolved at 100x the
required concentration in 0.1 M sodium hydroxide before dilution with
appropriate media.
Nitrite assay
Nitrite accumulation in culture medium was used as a measure of cellular NO synthesis (17). This was assessed spectrophotometrically by addition of 100 µl of Griess reagent (1% sulfanilamide and 0.1% N-(1-naphthyl)ethylenediamine in 5% o-phosphoric acid; Sigma Chemical) to an equal volume of sample medium in 96-well plates. Optical densities were measured by dual wavelength analysis (OD 570–630 nm) in a plate reader (Biotek EL-310; Biotek Instruments, Winooski, VT); sodium nitrite was used as standard.
Cell viability assay
Cell viability was assessed by measuring the ability of macrophages to reduce 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium (MTT) at the end of experimental procedures (18). 5 mg/ml MTT (Sigma Chemical) was added to each well to give a final concentration of 0.5 mg/ml, and cells were incubated for 20 min, the medium removed, and the formazan product dissolved in 100 µl DMSO. Product formation was assessed spectrophotometrically by measuring the OD at a dual wavelength (OD 570–630 nm) in a plate reader (Biotek EL-310).
Western blotting
Test medium was removed from culture flasks and cells resuspended by cell scraper in 2 ml of fresh medium. Cells were pelleted by centrifugation (200 x g, 4°C for 10 min), resuspended in 200 µl of ice-cold protease inhibitory buffer (1 mM PMSF, 1.5 mM pepstatin A, 0.2 mM leupeptin in 0.05 M Tris buffer, pH 7.4; Sigma Chemical), and sonicated. Protein concentrations of samples was determined by Bradford assay (Bio-Rad, Hemel Hempstead, U.K.) and samples equilibrated to 2 mg/ml with protease inhibitory buffer. An equal volume of Laemmli loading buffer was added, and samples were boiled for 5 min. Samples were loaded on 7.5% gels for SDS-PAGE for iNOS, glucose-regulated protein 78 (GRP78), HSP70, and COX-2 and 15% gels for HO-1 and HO-2. Proteins were electroeluted onto nitrocellulose membrane (Hybond C Super, 0.45 µm, Amersham, Little Chalfont, U.K.). Protein expression was visualized by enhanced chemiluminescent detection (ECL; Amersham). The following polyclonal primary Abs and dilutions were used: rabbit anti-mouse iNOS, 1:5000 (Santa Cruz Biotechnology, Santa Cruz, CA); rabbit anti-rat HO-1, 1:2000, rabbit anti-rat HO-2, 1:2000, and rabbit anti-rat GRP78, 1:2000 (Stressgen Biotechnologies, Victoria, Canada); rabbit anti-mouse COX-2, 1:3000 (Caymen Chemical); rabbit anti-human HSP70, 1:4000 (Dako, High Wycombe, U.K.). Anti-rabbit IgG for ECL (Amersham) was used at dilutions of 1:2000 for HO-1, HO-2, and GRP78, 1:3000 for COX-2, and 1:4000 for iNOS and HSP70. Bands were recorded on x-ray film (Fuji RX, Genetic Research Instrumentation, Dunmow, U.K.) for permanent record. Representative blots from three experiments are presented.
Statistical analysis
Results are representative of three experiments with n = 6 in each group. Significance of data was examined by analysis of variance (ANOVA) followed by a post hoc Bonferroni-corrected t test (Instat, GraphPad Software, University of Amsterdam, The Netherlands).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Stimulation of macrophages with IFN- and LPS routinely
increased nitrite levels in medium by >12-fold after 18 h,
compared with nonstimulated cultures (data not shown). Viability of
cell cultures (Fig. 1
) treated with up to
10 µg/ml of LTB4,
8(S)-hydroxyeicosatetraenoic acid
(8(S)-HETE), PGA2,
PGD2, and PGJ2 was not affected. However,
Wy14,643 was found to be toxic at a concentration of 100 µg/ml,
although no effect on viability was observed at 30 µg/ml or below.
12PGJ2 reduced viability at 10 µg/ml. Only
data derived from nontoxic doses of compounds was considered,
therefore, in subsequent analysis of the results.
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). In
contrast, Wy14,643 dose dependently reduced nitrite accumulation,
causing a significant 60% decrease at the highest nontoxic dose of 30
µg/ml.
At doses shown to be nontoxic, all PGs tested proved capable of
inhibiting iNOS activity at the higher doses investigated, indicated by
a reduction in nitrite accumulation in test medium (Fig. 2). PGA2 at doses up to 1
µg/ml significantly increased nitrite production. Above this level,
nitrite production was reduced, with a 94% reduction at 10 µg/ml.
PGD2 did not elevate nitrite accumulation at low doses, but
dose dependently reduced nitrite accumulation. This reached
significance at 1 µg/ml, and nitrite levels fell by 51% at 10
µg/ml. PGJ2 elicited a response similar to that of
PGD2, although significance was not reached until 3
µg/ml, with a 69% fall at 10 µg/ml.
12PGJ2 was the most potent inhibitor of
nitrite accumulation, with reaching significance at 30 ng/ml, and an
81% reduction at the highest nontoxic dose of 3 µg/ml. For
subsequent analysis of changes in protein expression in response to
PPAR agonist treatment, the response to the most potent inhibitor of
iNOS, 12PGJ2, was investigated.
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12PGJ2 on stimulated RAW264.7
macrophages
Stimulation of macrophages with IFN- and LPS markedly increased
iNOS protein expression at 18 h poststimulation (Fig. 3). At doses up to 0.3 µg/ml,
12PGJ2 did not affect this level visibly.
Above this dosage, however, iNOS protein levels fell markedly, with
little expression visible, compared with stimulated control cultures at
the highest nontoxic dose of 3 µg/ml. These changes in iNOS
expression correlated with changes in the levels of HO-1 present in
these macrophages. Thus, at low doses, induction of HO-1 protein
expression was evident, but increased markedly at concentrations of
12PGJ2 of 0.3 µg/ml and above. Additional
lower m.w. bands seen at 3 µg/ml and 10 µg/ml are breakdown
products of HO-1 (4).
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and LPS, but although minor variations in protein levels were
observed, no consistent effect on protein expression was seen in the
presence of 12PGJ2 compared with stimulated
control cultures, with no evidence of a dose-dependent effect (data not
shown). Expression of HO-2, HSP70, and GRP78 (Fig. 3) were also
unaffected either by stimulation or by treatment with
12PGJ2.
Western blot analysis of the time-dependent effects of 3
µg/ml 12PGJ2 on stimulated RAW264.7
macrophages
Analysis of the time course of protein expression was conducted
using the highest nontoxic dose of
12PGJ2, 3 µg/ml. In non-PG-treated
cultures, stimulation with IFN- and LPS increased iNOS expression
(Fig. 4), this effect being evident at
6 h, greatest at 12 h, and slightly reduced at 24 h.
HO-1 was similarly induced (Fig. 4), with a longer delay before protein
expression was enhanced, this being evident at 12 h and most
notable at 24 h.
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12PGJ2 caused a retardation
in iNOS expression, with increased expression first evident at 9 h
poststimulation, and the greatest response seen at 24 h (Fig. 4).
This correlated with an earlier induction of HO-1, with much increased
expression of this protein seen at 6 through 12 h poststimulation.
This increased expression was lost at 24 h poststimulation in
12PGJ2-treated cultures.
In keeping with the results reported above, expression of COX-2 was
increased by stimulation with IFN- and LPS, this being evident at
3 h and maintained through to 24 h. Variation in protein
expression between control and treated cultures was seen, but no
consistent pattern in the temporal changes was observed over the three
experiments, and it was concluded that COX-2 expression was unaffected
by the presence of 12PGJ2 (data not shown).
As seen previously, neither stimulation nor the presence of the PG
affected the expression of HO-2, HSP70, and GRP78 at any time point
examined (Fig. 4).
The effect of ZnDPP on the inhibition of nitrite release by
12PGJ2
Given the correlation between iNOS expression and HO-1 seen in the
Western blot analysis, the effect of including a selective HO
inhibitor, ZnDPP, was examined. As shown previously, addition of
12PGJ2 at doses up to 3 µg/ml was
without effect on viability of macrophages stimulated with IFN- and
LPS (Fig. 5). Addition of ZnDPP alone, at
concentrations up to 30 µM, to stimulated cultures did not affect
viability nor change nitrite accumulation in the medium (data not
shown). In cultures treated with 12PGJ2,
ZnDPP at 30 µM similarly did not affect viability (Fig. 5).
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), with a 79%
reduction seen at 3 µg/ml of 12PGJ2.
Inclusion of ZnDPP partially reversed these effects, the inhibitory
effect of 12PGJ2 being approximately halved
(43% reduction in nitrite accumulation with 3 µg/ml
12PGJ2, compared with stimulated controls in
the presence of this inhibitor). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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agonists are able to inhibit iNOS
activity, measured by a reduction in nitrite accumulation and iNOS
protein expression in macrophages, an effect that correlates with
activation of HO-1. iNOS, inducible HO, the stress proteins, and the inducible COX-2 are several key physiologic and pathophysiologic systems that have stimulated much interest in recent years (2, 19). In particular, the interplay between these systems has been the subject of much debate, not only because of the possibilities of using them as therapeutic targets, but also the possible ramifications of interfering with any one of them. The recent discovery of the possibility of peroxisomal control of inflammation (15), by modulating the destruction of key mediators of the inflammatory response such as the leukotrienes and other prostanoids, has offered another possibility to the anti-inflammatory armory currently under development. To date, the effects of many of the PPAR agonists on iNOS, a key enzyme system in inflammation and other pathologies, have not been reported.
Initial studies investigated the role of the PPARs on the production of
NO by stimulated RAW264.7 macrophages, which are used in many in vitro
studies (20). This was conducted using a variety of naturally occurring
eicosanoids, LTB4, 8(S)-HETE,
PGA2, PGD2, PGJ2, and
PG12J2, as well as the PPAR-selective
compound Wy14,643 to screen for their effects on nitrite production,
indicative of activity of the iNOS pathway. LTB4 and
8(S)-HETE, which activate PPAR (15) and are
described as poor activators of PPAR, showed no inhibitory activity,
but at high concentrations caused a stimulation of nitrite
accumulation. In the case of LTB4, this has been
demonstrated for human neutrophils using a lower dose of 0.1 µM (21).
In RAW264.7 macrophages, LTB4 has been reported to have no
effect on iNOS activity, although a concentration of only 1 nM was
investigated (22). The ability to inhibit nitrite accumulation of some
of the other compounds examined was shown not to be related to their
cytotoxic potential, although this phenomenom was evident at higher
concentrations. Wy14,643, also described as PPAR selective (23),
only inhibited nitrite accumulation, unlike LTB4 and
8(S)-HETE. It is therefore possible that the
stimulatory effects of these latter two are not related to PPAR
activation. Inhibition with Wy14,643 was, however, effective only at
much higher concentrations than the PGs tested. It is known, however,
that Wy14,643 is a less efficient PPAR-binding ligand and is capable
of also activating PPAR at the concentrations used here to inhibit
nitrite accumulation (24). In contrast, the cyclopentenone PGs were
effective inhibitors. The cyclopentenone PGA2 inhibited
nitrite accumulation at higher concentrations, but at lower
concentrations PGA2 increased nitrite accumulation. The
reason behind this effect is unclear. However, PGE2, the
precursor of PGA2, has been shown to both increase iNOS
activity at low concentrations and inhibit them at high concentrations
in a similar fashion (25). PGD2 and it’s metabolites of
the PGJ2 series are selective activators of the PPAR
receptor pathway (26) and were demonstrated to inhibit iNOS. The data
presented in this study suggest, therefore, that in these macrophages,
it is PPAR activation that is responsible for the effects described.
This adds to the previously published in vivo data suggesting that
PPAR activation is also an important pathway for
anti-inflammatory activity (15).
Further studies into the mechanism behind this inhibition used
the technique of Western blotting to examine the levels of protein
expressed by these macrophages in response to treatment with
12PGJ2, the most potent inhibitor of nitrite
accumulation activity investigated. Previously published work has
revealed a link between these PGs and the induction of the stress
response in a variety of cell lines (5, 12). We have previously
published the observation that control of HO-1 activity can also affect
the outcome of inflammation (4). In this study, it was shown that
induction of HO-1 could markedly suppress an acute inflammatory
reaction. In addition, work within this department has shown that the
iNOS and HO-1 pathways exhibit a degree of interdependency
(27).
Examination of HO-1 expression elicited by
12PGJ2 revealed a correlation between the
degree of inhibition of iNOS and the extent of induction of HO-1. Other
markers of the stress response, HSP70 and GRP78, were unaffected by
this treatment. Although HSP70 has been shown to be induced by these
PGs in human lines, this feature has been reported absent in murine
cell lines (28). Similarly, levels of HO-2, which has been described as
a constitutively expressed protein (29), were unchanged. There was no
correlation between the inhibition of iNOS and the expression of COX-2,
although cyclopentenone PGs have been shown to induce this enzyme in
murine liver cell lines (30). This induction could not be demonstrated
in the current study using murine macrophages. The possibility that
induction of COX-2 may play a role in the anti-inflammatory
properties of these PGs and/or PPAR activation remains to be
investigated. One possible mechanism in which this may be important may
involve the generation of these "anti-inflammatory
prostaglandins" at later time points in inflammation. In mast cells,
COX-2 has been shown to exhibit different modes of arachidonic acid
acquisition compared with COX-1 and is responsible for late phase,
sustained release of PGD2 (31). This is the precursor for
the PGJ series, which are formed spontaneously from PGD2 in
biologic fluids in the presence of albumin (32), and may represent a
negative feedback loop for inflammation control by eicosanoid breakdown
products. In the carrageenan pleurisy, Western blotting reveals two
distinct peaks in protein expression. An early peak is associated with
PGE2 production, while a late peak is also found that is
not associated with PGE2 elaboration (D.W., unpublished
observations). The role of this latter peak in this model is the
subject of current study, but it is possible that this peak may
represent a new function for COX-2 during resolution by producing
prostanoids that may help to terminate inflammation.
The time courses of these changes in the level of these proteins were constructed to attempt to further correlate any changes seen. In non-PG-treated cells, iNOS protein was evident at 6 h and peaked at 18 h, with a fall at 24 h, in agreement with previously published data (20). Inducible HO protein levels did not rise until 24 h; this correlated with the fall in iNOS protein expression seen at the same time point. In PG-treated cells, the expression of HO-1 was increased and also temporally shifted such that expression was seen much earlier, at 6 to 9 h. In keeping with a possible link between the two systems, iNOS induction was retarded until the HO-1 levels were reduced at 24 h. This latter finding has potential importance for the development of a therapeutic approach, due to the short period of suppression of iNOS seen in these cultures. However, it is known that the half-life of these PGs in vitro is extremely short, and it is possible that HO-1 expression was maintained only for as long as they were present, with later escape of the iNOS response due to the greater stability of the stimulus for iNOS in the culture system used. Again, no correlation was seen between the inhibition of iNOS and the expression of HSP70, GRP78, HO-2, or COX-2.
Given the possible link demonstrated between the induction of HO-1 and the inhibition of iNOS, the effect of ZnDPP, a specific HO-1 inhibitor (33), was examined in the whole cell system used initially. ZnDPP was shown to have no effect on cell viability nor on iNOS activity in this system in the absence of treatment with the PG. However, when ZnDPP was included with the PG, the inhibitory effect of the PG was reduced to half that seen in the presence of the PG alone, suggesting that at least part of this inhibitory activity was due to activation of HO-1. The remainder may represent a more direct action of the PG on iNOS induction, although to date no peroxisome proliferator response element has been described on the iNOS promoter.
The precise mechanism whereby the interaction between HO-1 and iNOS is
effected is unknown and will be the subject of further work. It has
been shown that the antiproliferative cyclopentenone PGA1
activates HSF, which subsequently induced the expression of HSP70 and
HSP90 genes (5, 12). Activation of HSF could potentially modulate a
variety of gene products that possess a heat shock element. Thus,
activation of the heat shock element up-regulates the production of
HO-1 (34) and other stress proteins such as HSP70 and HSP90, which may
be anti-inflammatory, but also inhibits production of other
pro-inflammatory cytokines such as IL-1 (35). With particular reference
to iNOS activation, it is well documented that the heat shock response
(36) and HSP70 (37) are capable of inhibiting this enzyme system, the
latter by decreasing NF
B activation. These two enzyme systems are
also coinduced in macrophages (38), HO-1 induction having been
suggested as protective against the harmful effects of nitric oxide
production. Although HSP70 was not induced in these murine cells by
these PGs, in other mammalian systems and in man, such a mechanism may
be of import. HO-1 activation may have further effects on inflammation
via the production of heme breakdown products (4); these include CO,
which may inhibit iNOS activity by binding to and inactivating the heme
moiety on the enzyme; biliverdin and bilirubin, which may scavenge
product by direct antioxidant effects; and iron, which will affect
cellular redox potentials. Elevations in anti-oxidant molecules may
also stabilize inhibitory factor B-NFB complexes and lead to a
reduction in active NFB, a factor that is required for iNOS
induction (39). Work is in progress on these possibilities.
Although the levels of cyclopentenone PGs used in this study are high in comparison with most studies using conventional eicosanoids, it is known that there are selective uptake mechanisms for these PGs in cells, which can enhance their intracellular concentration (40). In addition, assays in vivo show that micromolar levels of cyclopentenone can be demonstrated in homogenates of most normal tissues, particularly the spleen (41). This is of particular note as this is a tissue that expresses one of the highest levels of HO-1 in the body, where it is associated with destruction of heme from erythrocytes.
Although no evidence for the direct involvement of PPARs in this study
has been demonstrated here, it is currently being investigated, and the
literature suggests that the cyclopentenone PGs and Wy14,643 are PPAR
ligands and may exert their actions via activation of these nuclear
receptors. Together with the data presented in this paper, this
suggests that the PPAR pathway may provide a novel and viable point of
therapeutic intervention into the control of a wide variety of
inflammatory diseases and other pathologies. In particular, the
efficacy of those ligands that have selectivity for PPAR suggests
that this is the pathway that may be of import in controlling certain
aspects of the inflammatory
process.4
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Footnotes |
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2 Address correspondence and reprint requests to Dr D. Willis, Department of Experimental Pathology, St. Bartholomew’s and The Royal London School of Medicine and Dentistry, Charterhouse Square, London, EC1 M 6BQ, U.K. E-mail address:
3 Abbreviations used in this paper: COX, cyclooxygenase; NOS, nitric oxide synthase; iNOS, inducible nitric oxide synthase; NO, nitric oxide; HSP, heat shock proteins; HO, heme oxygenase; PPAR, peroxisome proliferator-activated receptor; HSF, heat shock factor; LTB4, leukotriene B4; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium; GRP78, glucose-regulated protein 78; 8(S)-HETE, 8 hydroxy-5,9,11,14-eicosatetraenoic acid; ZnDPP, zinc deuteroprotoporphyrin.
4 Subsequent to the submission of this paper for review, two papers have been published that support an anti-inflammatory role for PPAR agonist: M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass. 1998. The peroxisome proliferator activated receptor- is a negative regulator of macrophage activation. Nature 391:79; and C. Jiang, A. T. Ting, and B. Seed. 1998. PPAR- agonists inhibit production of monocyte inflammatory cytokines. Nature 392:82.
Received for publication November 12, 1997. Accepted for publication March 23, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 B. Martinez, A. Perez-Castillo, and A. Santos The mitochondrial respiratory complex I is a target for 15-deoxy-{Delta}12,14-prostaglandin J2 action J. Lipid Res., April 1, 2005; 46(4): 736 - 743. [Abstract] [Full Text] [PDF]
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 M. Abdelrahman, A. Sivarajah, and C. Thiemermann Beneficial effects of PPAR-{gamma} ligands in ischemia-reperfusion injury, inflammation and shock Cardiovasc Res, March 1, 2005; 65(4): 772 - 781. [Abstract] [Full Text] [PDF]
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 I. E. Camacho, L. Serneels, K. Spittaels, P. Merchiers, D. Dominguez, and B. De Strooper Peroxisome Proliferator-Activated Receptor {gamma} Induces a Clearance Mechanism for the Amyloid-{beta} Peptide J. Neurosci., December 1, 2004; 24(48): 10908 - 10917. [Abstract] [Full Text] [PDF]
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S. M. Weber, K. T. Chambers, K. G. Bensch, A. L. Scarim, and J. A. Corbett PPAR{gamma} ligands induce ER stress in pancreatic {beta}-cells: ER stress activation results in attenuation of cytokine signaling Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1171 - E1177. [Abstract] [Full Text] [PDF]
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 S.-Y. Lim, J.-H. Jang, H.-K. Na, S. C. Lu, I. Rahman, and Y.-J. Surh 15-Deoxy-{Delta}12,14-Prostaglandin J2 Protects against Nitrosative PC12 Cell Death through Up-regulation of Intracellular Glutathione Synthesis J. Biol. Chem., October 29, 2004; 279(44): 46263 - 46270. [Abstract] [Full Text] [PDF]
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G. F. Watts and B. Staels Regulation of Endothelial Nitric Oxide Synthase by PPAR Agonists: Molecular and Clinical Perspectives Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 619 - 621. [Full Text] [PDF]
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S. M. Weber, A. L. Scarim, and J. A. Corbett PPAR{gamma} is not required for the inhibitory actions of PGJ2 on cytokine signaling in pancreatic {beta}-cells Am J Physiol Endocrinol Metab, March 1, 2004; 286(3): E329 - E336. [Abstract] [Full Text]
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G. Kronke, V. N. Bochkov, J. Huber, F. Gruber, S. Bluml, A. Furnkranz, A. Kadl, B. R. Binder, and N. Leitinger Oxidized Phospholipids Induce Expression of Human Heme Oxygenase-1 Involving Activation of cAMP-responsive Element-binding Protein J. Biol. Chem., December 19, 2003; 278(51): 51006 - 51014. [Abstract] [Full Text] [PDF]
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 B. OSTERUD and E. BJORKLID Role of Monocytes in Atherogenesis Physiol Rev, October 1, 2003; 83(4): 1069 - 1112. [Abstract] [Full Text] [PDF]
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T.-S. Lee, H.-L. Tsai, and L.-Y. Chau Induction of Heme Oxygenase-1 Expression in Murine Macrophages Is Essential for the Anti-inflammatory Effect of Low Dose 15-Deoxy-{Delta}12,14-prostaglandin J2 J. Biol. Chem., May 23, 2003; 278(21): 19325 - 19330. [Abstract] [Full Text] [PDF]
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S. M. Weber, A. L. Scarim, and J. A. Corbett Inhibition of IFN-gamma -induced STAT1 activation by 15- deoxy-Delta 12,14-prostaglandin J2 Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E883 - E891. [Abstract] [Full Text] [PDF]
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 E. Cernuda-Morollon, F. Rodriguez-Pascual, P. Klatt, S. Lamas, and D. Perez-Sala PPAR Agonists Amplify iNOS Expression While Inhibiting NF-{kappa}B: Implications for Mesangial Cell Activation by Cytokines J. Am. Soc. Nephrol., September 1, 2002; 13(9): 2223 - 2231. [Abstract] [Full Text] [PDF]
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 K. Reynolds, B. Novosad, A. Hoffhines, J. Gipson, J. Johnson, J. Peters, F. Gonzalez, J. Gimble, and M. Hill Pretreatment with troglitazone decreases lethality during endotoxemia in mice Innate Immunity, August 1, 2002; 8(4): 307 - 314. [Abstract] [PDF]
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S. Cuzzocrea, N. S. Wayman, E. Mazzon, L. Dugo, R. Di Paola, I. Serraino, D. Britti, P. K. Chatterjee, A. P. Caputi, and C. Thiemermann The Cyclopentenone Prostaglandin 15-Deoxy-Delta 12,14-Prostaglandin J2 Attenuates the Development of Acute and Chronic Inflammation Mol. Pharmacol., May 1, 2002; 61(5): 997 - 1007. [Abstract] [Full Text] [PDF]
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 D. G. Alleva, E. B Johnson, F. M Lio, S. A Boehme, P. J Conlon, and P. D. Crowe Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for peroxisome proliferator-activated receptor-{gamma}: counter-regulatory activity by IFN-{gamma} J. Leukoc. Biol., April 1, 2002; 71(4): 677 - 685. [Abstract] [Full Text] [PDF]
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R. B. Clark The role of PPARs in inflammation and immunity J. Leukoc. Biol., March 1, 2002; 71(3): 388 - 400. [Abstract] [Full Text] [PDF]
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 S. G. Harris, R. S. Smith, and R. P. Phipps 15-Deoxy-{Delta}12,1412,14-PGJ2 Induces IL-8 Production in Human T Cells by a Mitogen-Activated Protein Kinase Pathway J. Immunol., February 1, 2002; 168(3): 1372 - 1379. [Abstract] [Full Text] [PDF]
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 M.-A. Simonin, K. Bordji, S. Boyault, A. Bianchi, E. Gouze, P. Becuwe, M. Dauca, P. Netter, and B. Terlain PPAR-gamma ligands modulate effects of LPS in stimulated rat synovial fibroblasts Am J Physiol Cell Physiol, January 1, 2002; 282(1): C125 - C133. [Abstract] [Full Text] [PDF]
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 T. Tanaka, H. Kohno, S.-i. Yoshitani, S. Takashima, A. Okumura, A. Murakami, and M. Hosokawa Ligands for Peroxisome Proliferator-activated Receptors {{alpha}} and {{gamma}} Inhibit Chemically Induced Colitis and Formation of Aberrant Crypt Foci in Rats1 Cancer Res., March 1, 2001; 61(6): 2424 - 2428. [Abstract] [Full Text]
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 T. Claudel, M. D. Leibowitz, C. Fiévet, A. Tailleux, B. Wagner, J. J. Repa, G. Torpier, J.-M. Lobaccaro, J. R. Paterniti, D. J. Mangelsdorf, et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor PNAS, February 15, 2001; (2001) 41609298. [Abstract] [Full Text]
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 A. VON KNETHEN and B. BRUNE Delayed activation of PPAR{gamma} by LPS and IFN-{gamma} attenuates the oxidative burst in macrophages FASEB J, February 1, 2001; 15(2): 535 - 544. [Abstract] [Full Text] [PDF]
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 M Cavicchi, L Gibbs, and B J R Whittle Inhibition of inducible nitric oxide synthase in the human intestinal epithelial cell line, DLD-1, by the inducers of heme oxygenase 1, bismuth salts, heme, and nitric oxide donors Gut, December 1, 2000; 47(6): 771 - 778. [Abstract] [Full Text] [PDF]
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M. T. Heneka, T. Klockgether, and D. L. Feinstein Peroxisome Proliferator-Activated Receptor-gamma Ligands Reduce Neuronal Inducible Nitric Oxide Synthase Expression and Cell Death In Vivo J. Neurosci., September 15, 2000; 20(18): 6862 - 6867. [Abstract] [Full Text] [PDF]
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 M. N. Ajuebor, A. Singh, and J. L. Wallace Cyclooxygenase-2-derived prostaglandin D2 is an early anti-inflammatory signal in experimental colitis Am J Physiol Gastrointest Liver Physiol, July 1, 2000; 279(1): G238 - G244. [Abstract] [Full Text] [PDF]
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U. Ikeda, M. Shimpo, Y. Murakami, and K. Shimada Peroxisome Proliferator-Activated Receptor-{gamma} Ligands Inhibit Nitric Oxide Synthesis in Vascular Smooth Muscle Cells Hypertension, June 1, 2000; 35(6): 1232 - 1236. [Abstract] [Full Text] [PDF]
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K. Bordji, J.-P. Grillasca, J.-N. Gouze, J. Magdalou, H. Schohn, J.-M. Keller, A. Bianchi, M. Dauca, P. Netter, and B. Terlain Evidence for the Presence of Peroxisome Proliferator-activated Receptor (PPAR) alpha and gamma and Retinoid Z Receptor in Cartilage. PPARgamma ACTIVATION MODULATES THE EFFECTS OF INTERLEUKIN-1beta ON RAT CHONDROCYTES J. Biol. Chem., April 14, 2000; 275(16): 12243 - 12250. [Abstract] [Full Text] [PDF]
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 A. Castrillo, M. J. M. Díaz-Guerra, S. Hortelano, P. Martín-Sanz, and L. Boscá Inhibition of Ikappa B Kinase and Ikappa B Phosphorylation by 15-Deoxy-Delta 12,14-Prostaglandin J2 in Activated Murine Macrophages Mol. Cell. Biol., March 1, 2000; 20(5): 1692 - 1698. [Abstract] [Full Text]
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R. B. Clark, D. Bishop-Bailey, T. Estrada-Hernandez, T. Hla, L. Puddington, and S. J. Padula The Nuclear Receptor PPAR{gamma} and Immunoregulation: PPAR{gamma} Mediates Inhibition of Helper T Cell Responses J. Immunol., February 1, 2000; 164(3): 1364 - 1371. [Abstract] [Full Text] [PDF]
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C. M. Reilly, J. C. Oates, J. A. Cook, J. D. Morrow, P. V. Halushka, and G. S. Gilkeson Inhibition of Mesangial Cell Nitric Oxide in MRL/lpr Mice by Prostaglandin J2 and Proliferator Activation Receptor-{gamma} Agonists J. Immunol., February 1, 2000; 164(3): 1498 - 1504. [Abstract] [Full Text] [PDF]
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P. Delerive, K. De Bosscher, S. Besnard, W. Vanden Berghe, J. M. Peters, F. J. Gonzalez, J.-C. Fruchart, A. Tedgui, G. Haegeman, and B. Staels Peroxisome Proliferator-activated Receptor alpha Negatively Regulates the Vascular Inflammatory Gene Response by Negative Cross-talk with Transcription Factors NF-kappa B and AP-1 J. Biol. Chem., November 5, 1999; 274(45): 32048 - 32054. [Abstract] [Full Text] [PDF]
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N. Klocker, P. Kermer, M. Gleichmann, M. Weller, and M. Bahr Both the Neuronal and Inducible Isoforms Contribute to Upregulation of Retinal Nitric Oxide Synthase Activity by Brain-Derived Neurotrophic Factor J. Neurosci., October 1, 1999; 19(19): 8517 - 8527. [Abstract] [Full Text] [PDF]
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 N. Callejas, M Casado, L Bosca, and P Martin-Sanz Requirement of nuclear factor kappaB for the constitutive expression of nitric oxide synthase-2 and cyclooxygenase-2 in rat trophoblasts J. Cell Sci., January 9, 1999; 112(18): 3147 - 3155. [Abstract] [PDF]
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P. Gervois, N. Vu-Dac, R. Kleemann, M. Kockx, G. Dubois, B. Laine, V. Kosykh, J.-C. Fruchart, T. Kooistra, and B. Staels Negative Regulation of Human Fibrinogen Gene Expression by Peroxisome Proliferator-activated Receptor alpha Agonists via Inhibition of CCAAT Box/Enhancer-binding Protein beta J. Biol. Chem., August 31, 2001; 276(36): 33471 - 33477. [Abstract] [Full Text] [PDF]
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T. Claudel, M. D. Leibowitz, C. Fievet, A. Tailleux, B. Wagner, J. J. Repa, G. Torpier, J.-M. Lobaccaro, J. R. Paterniti, D. J. Mangelsdorf, et al. Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor PNAS, February 27, 2001; 98(5): 2610 - 2615. [Abstract] [Full Text] [PDF]
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