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* Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, and
Solution-Oriented Research for Science and Technology of Japan Science and Technology Corp., Suita, Osaka, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-12. Membrane-bound
glutathione-dependent PGE2 synthase (mPGES) has been shown
to be a terminal enzyme of the cyclooxygenase-2-mediated
PGE2 biosynthesis. Here we identified mPGES as a molecule
that is induced by LPS in macrophages. The expression of mPGES was not
induced by LPS in mice lacking Toll-like receptor 4 or MyD88.
Furthermore, mice deficient in NF-IL6 showed neither induction of mPGES
nor biosynthesis of PGE2 in response to LPS, indicating
that mPGES expression in response to LPS is regulated by a Toll-like
receptor 4/MyD88/NF-IL6-dependent signaling pathway. We generated
mPGES-deficient mice and investigated the role of mPGES in vivo. The
mice showed no augmentation of the PGE2 production in
response to LPS. However, they were not impaired in the LPS-induced
production of inflammatory cytokines and showed normal response to the
LPS-induced shock. Thus, mPGES is critically involved in the
biosynthesis of PGE2 induced by LPS, but is dispensable for
the modulation of inflammatory responses. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study we identified mPGES/MGST1-L1 as a LPS-inducible gene in macrophages by a suppression subtractive hybridization technique. We showed that LPS-induced mPGES expression is regulated through a Toll-like receptor 4 (TLR4)/MyD88-dependent pathway and entirely depends upon the NF-IL6 transcription factor. Furthermore, we generated mice deficient in mPGES and demonstrated that mPGES/MGST1-L1 is essential for delayed PGE2 synthesis by activated macrophages in response to LPS.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LPS from Salmonella minnesota
Re-595 prepared by a phenol-chloroform-petroleum ether extraction
procedure was purchased from Sigma-Aldrich (St. Louis, MO).
Thioglycolate broth (Brewer’s formula) was purchased from Difco
(Detroit, MI). IFN-
was obtained from Genzyme (Cambridge, MA).
Restriction and DNA modification enzymes were products of TOYOBO
(Tsuruga, Japan).
Subtractive hybridization
RAW264.7 (1 x 108) cells were stimulated with LPS (100 ng/ml) for 4 h. RNA was obtained from the cells with an RNA easy kit (Qiagen, Hilden, Germany) following poly(A)+ RNA selection using Oligotex-dT30 latex beads (Takara, Otsu, Japan). Then all procedures were performed according to the instructions of the PCR-select cDNA subtraction kit (Clontech Laboratories, Palo Alto, CA).
Preparation of peritoneal macrophages
Peritoneal macrophages from wild-type, TLR4-mutant, MyD88-mutant, NF-IL6-mutant, and mPGES-mutant mice were isolated as described previously (12, 13, 14).
Northern blot analysis
Total RNA was extracted from peritoneal macrophages (5 x
106) using the TRIzol reagent (Invitrogen,
Carlsbad, CA). Then total RNA (5 µg) was electrophoresed, transferred
to a nylon membrane, and hybridized with
32P-labeled cDNA probe specific for mPGES, Cox-1,
Cox-2, and cPGES/p23 as described previously (14). The
same membrane was rehybridized with cDNA specific for 
-actin.
Western blot analysis
The cell lysates were separated on SDS-PAGE, transferred onto a nitrocellulose membrane, and incubated with the blocking buffer containing 5.0% skim milk. The membrane was incubated with the indicated Ab and then visualized with ECL system (NEN Life Science, Boston, MA).
RT-PCR
Total RNA was isolated from an adherent monolayer of peritoneal macrophages stimulated with LPS (100 ng/ml). cDNA synthesis was synthesized using Superscript II Moloney murine leukemia virus reverse transcriptase (Invitrogen). The cDNA product was amplified by primers for mPGES (5'-AGCACACTGCTGGTCATCAAGATGTAC-3' and 5'-CCTGAGAGGACAACGAGGAAATGTATC-3').
Generation of mPGES-mutant mice
Membrane-associated PGES genomic DNA was screened from a 129/SvJ
mouse genomic library (Stratagene, La Jolla, CA), subcloned into
pBluescript vector (Stratagene), and characterized by restriction
enzyme mapping and DNA sequencing. A targeting vector was constructed
to replace the 1.2-kb genomic fragment containing the second exon with
the neomycin resistance gene from pMC1-neo (Stratagene). The targeting
vector was flanked by the 5.5-kb 5' genomic fragment and the 1.2-kb 3'
fragment and contained an HSV-thymidine kinase cassette at the 5' end
of the vector. The targeting vector was linearized with SalI
and electroporated into E14.1 embryonic stem (ES) cells. The clones
resistant to G418 and gancycrovir were screened for homologous
recombination by PCR and confirmed by Southern blot analysis using the
probe indicated in Fig. 2
A. The mutant mice were essentially
generated as described previously (12).
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To evaluate the production of cytokines by macrophages in vitro,
thioglycolate-elicited peritoneal cells were seeded onto 96-well plates
(2 x 105 cells/well) and stimulated with
the indicated reagents for 24 h. Concentrations of TNF-,
IL-12p40, and IL-6 were measured by ELISA according to the
manufacturer’s instructions (Genzyme, Cambridge, MA). Production of
PGE2 was measured with a
PGE2 monoclonal enzyme immunoassay kit (Cayman
Chemicals, Ann Arbor, MI). For the in vivo experiments wild-type and
mPGES-mutant mice were i.p. injected with 0.1 ml PBS containing 1 mg
LPS, and sera were taken at the indicated time points. Serum levels of
TNF-, IL-12p40, and PGE2 were determined by
ELISA.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To identify the LPS-inducible genes responsible for immune and
inflammatory responses in activated macrophages we prepared a cDNA
library from LPS-stimulated cells of the mouse macrophage line,
RAW264.7, and screened the library by a suppression-subtracted
hybridization technique. Using this technique we previously identified
novel LPS-inducible genes such as the LPS-inducible CCR and inducible
I
B kinase genes (15, 16). In addition we obtained a
gene encoding membrane-bound glutathione-dependent
PGE2 synthase (mPGES). We examined the expression
of mPGES in response to LPS in mouse peritoneal macrophages.
Thioglycolate-elicited peritoneal macrophages were treated with 100
ng/ml LPS for 0.5, 2, 8, and 16 h, and the mRNA expression of
mPGES was examined by Northern blot analysis. As shown in Fig. 1A, mRNA for mPGES was not
detected in nonstimulated macrophages, but was markedly expressed in
response to LPS. Four major transcripts were detected, and the shortest
one matched the mouse mPGES cDNA (accession no. AB041997) in length.
The mRNA expression of mPGES was induced at 2 h, reached a peak at
8 h, and lasted until 16 h.
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B). NF-IL6-deficient macrophages are defective in the LPS-induced expression of mPGES
When macrophages are activated by various inflammatory stimuli,
NF-IL6 exhibits the augmented transcriptional activity and plays an
important role in inflammatory responses of the macrophages
(17). NF-IL6 binding motifs have been identified in the
promoter regions of several LPS-inducible genes, including Cox-2
(18, 19, 20). Therefore, we analyzed the LPS-induced
expression of mPGES in NF-IL6-deficient macrophages. Peritoneal
macrophages from wild-type and NF-IL6-deficient mice were stimulated
with LPS, and the expression of mPGES was examined by Northern
blotting. In NF-IL6-deficient macrophages, LPS-induced expression of
mPGES was almost completely abolished (Fig. 2A). We next examined the
expression of Cox-1, Cox-2, and cPGES/p23 in NF-IL6-deficient
macrophages. In wild-type macrophages Cox-1 mRNA was detected before
stimulation with LPS and was down-regulated after the stimulation (Fig. 2B). In contrast, Cox-2 mRNA was induced, reached a peak at
2 h, and then declined after 8 h in wild-type macrophages
stimulated by LPS (Fig. 2C). The expression of cPGES/p23
mRNA was detected before and augmented after the stimulation (Fig. 2B). In NF-IL6-deficient macrophages, down-regulation of
Cox-1 and up-regulation of cPGES/p23 were similarly observed (Fig. 2B). However, the LPS-induced expression of Cox-2 was
compromised in NF-IL6-deficient cells. At 2 h the expression of
Cox-2 mRNA was significantly reduced compared with that of wild-type
cells, although the expression of Cox-2 mRNA was increased at 8 h
in NF-IL6-deficient cells (Fig. 2C). We further analyzed
Cox-1 and Cox-2 protein expression in LPS-stimulated NF-IL6-deficient
peritoneal macrophages. Despite reduced expression of Cox-1 mRNA after
LPS stimulation, the protein level was not altered in wild-type or
NF-IL6-deficient macrophages (Fig. 2D, upper
panel). The expression of Cox-2 protein was induced at 12 h
and declined at 24 h in wild-type macrophages, whereas the
induction of Cox-2 protein in NF-IL6-deficient macrophages was observed
with delayed kinetics compared with wild-type macrophages (Fig. 2D, lower panel). Thus, severe impairment in
mPGES induction and delayed induction of Cox-2 were observed in
LPS-stimulated NF-IL6-deficient macrophages. We next analyzed the
production of PGE2 in macrophages from
NF-IL6-deficient mice. Thioglycolate-elicited peritoneal macrophages
were cultured with various concentrations of LPS for 24 h.
Nonstimulated cells secreted small amounts of
PGE2, and stimulation with LPS induced the
production of PGE2 in a dose-dependent manner in
wild-type mice. In NF-IL6-deficient macrophages, LPS did not induce the
production of PGE2, although nonstimulated cells
produced small amounts. These results indicate that NF-IL6 is involved
in the LPS-induced production of PGE2 by
mediating the gene expression of mPGES.
Generation of mPGES-deficient mice
To elucidate the role of mPGES in vivo, we generated mPGES-mutant
mice by gene targeting. The mouse mPGES gene was disrupted by
introducing a targeted mutation into E14.1 ES cells. A targeting vector
was designed to replace the second exon with the neomycin resistance
gene (Fig. 3A). This region of
the mPGES gene shows high homology with rat and human mPGES
(15). Homologous recombination was achieved in seven of
120 ES cell clones resistant to neomycin and ganciclovir. Three ES cell
lines containing a mutant mPGES allele were microinjected into C57BL/6
blastocysts. One line of these chimeric mice successfully transmitted
the disrupted mPGES gene through the germline. Homozygous mice carrying
the mutant allele were born at the expected Mendelian ratio (Fig. 3B). They were healthy and did not show any obvious
abnormalities until 20 wk. We investigated the expression of mPGES mRNA
in peritoneal macrophages stimulated with 100 ng/ml LPS for 8 h by
Northern blot analysis (Fig. 3C). We detected in the mutant
mice mPGES transcripts of almost the same size. We next conducted
RT-PCR using mRNA of LPS-stimulated macrophages from the mutant mice
(Fig. 3D). RT-PCR with primers that flank the cDNA coded by
the second exon resulted in the production of a 270-bp band in
wild-type mice and a 190-bp band in the mutant mice. Sequence analysis
of these products showed that second exon was completely deleted in
mRNA from the mutant mice, indicating that normal mPGES protein was not
produced in these animals (Fig. 3E).
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We first examined the production of PGE2 in
response to LPS in macrophages from mPGES-mutant mice.
Thioglycolate-elicited peritoneal macrophages were cultured with
various concentrations of LPS. Macrophages from mPGES-mutant mice
produced small amounts of PGE2, similar to
wild-type cells in the unstimulated condition (Fig. 4A). However, no LPS-induced
augmentation of PGE2 production was observed in
mPGES-mutant macrophages. This indicates that the targeted deletion of
the mPGES gene leads to a loss of functional protein production, and
that mPGES is essential for LPS-induced PGE2
production in macrophages.
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B). The serum level of
PGE2 was measured 6 h after injection. In
wild-type mice, the serum level of PGE2 increased
by 3-fold in response to LPS, whereas it remained at the basal level
after administration in mPGES-mutant mice. Taken together these results
demonstrate that mPGES is an indispensable enzyme for the production of
PGE2 in response to LPS. Normal production of proinflammatory cytokines in response to LPS in mPGES-mutant mice
PGE2 has been shown to modulate the
production of proinflammatory cytokines (21). Therefore,
we analyzed the LPS-induced production of proinflammatory cytokines in
mPGES-mutant mice. Thioglycolate-elicited peritoneal macrophages were
cultured with 100 ng/ml LPS in the presence or the absence of IFN-
(50 U/ml) for 24 h, and the production of TNF- IL-12p40 and
IL-6 was examined by ELISA (Fig. 5A). The production of these
cytokines in mPGES-mutant macrophages was comparable to that observed
in wild-type macrophages. We further examined in vivo the response to
LPS in wild-type and mPGES-deficient mice. Wild-type (n
= 3) or mPGES-mutant (n = 3) mice were i.p. injected
with 1 mg LPS. Sera were taken at the indicated time points, and
concentrations of TNF- and IL-12p40 were determined by ELISA (Fig. 5B). Both mice had significantly elevated serum
concentrations of these cytokines, and there was no difference in the
level of cytokine production between wild-type and mPGES-mutant mice.
We monitored the survival rate of mice after LPS administration. Almost
all wild-type and mPGES-mutant mice died within 5 days of the LPS
challenge (Fig. 5C). Thus, mPGES-mutant mice succumbed to
endotoxin shock despite showing no elevation of
PGE2.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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LPS-induced Cox-2 expression was observed with delayed kinetics in
NF-IL6-deficient macrophages. Transcriptional activation of the Cox-2
gene induced by LPS has been shown to partly depend on NF-IL6 in
macrophages. Indeed, NF-IL6 binding sites have been identified in the
promoter region of the Cox-2 gene (4, 25, 26, 27, 28). A recent
study showed that Cox-2 mRNA induction and promoter activity were
defective in NF-IL6-deficient macrophages, and the defect could be
rescued by the expression of NF-IL6 (26). Furthermore, it
has been demonstrated that Cox-2 mRNA induction is biphasic. The
initial phase of Cox-2 induction depends on NF-IL6, and the second
phase requires coordination of NF-IL6 and NF-IL6 in activated
macrophages (29). NF-B and cAMP response element CRE
have also been shown to regulate the expression of the Cox-2 gene
(25, 26, 27, 28). From these findings we speculate that the
reduced expression of Cox-2 during the early time period is due to the
absence of NF-IL6, but enhanced Cox-2 expression in the late period may
be due to compensation by other transcription factors. Although Cox-2
protein was significantly induced at the late time period of LPS
stimulation, PGE2 production was severely reduced
in NF-IL6-deficient macrophages. Thus, NF-IL6 is critically involved in
LPS-induced production of PGE2 through modulating
the expression of mPGES. In contrast, Cox-1 and cPGES/p23 induction was
not altered in NF-IL6-deficient macrophages. After LPS stimulation,
down-regulation of Cox-1 mRNA and up-regulation of cPGES/p23 mRNA were
observed. However, the protein level of Cox-1 was not changed after LPS
stimulation. At present, it remains unknown how LPS stimulation
down-regulates the expression of Cox-1 mRNA.
Generation of mPGES-mutant mice revealed an essential role for mPGES in the LPS-induced production of PGE2. A recent study showed that the kinetic change in PGE2 production correlated well with that in mPGES mRNA and protein expression and that dexamethasone reduced both PGE2 synthesis and mPGES expression in LPS-stimulated macrophages. This implies that the PGE2 production activity detected in LPS-stimulated macrophages is largely dependent on mPGES. PGE2 production in response to LPS was completely abolished in mPGES-mutant mice, demonstrating that mPGES is essential for LPS-induced biosynthesis of PGE2. Although LPS-induced PGE2 production was abolished in mPGES-mutant mice, the basal PGE2 level in mPGES-mutant mice was comparable to that in wild-type mice. This indicates that production of PGE2 at the basal level occurs independent of mPGES and mainly depends on Cox-1 and cPGES/p23, which are constitutively expressed. Indeed, mice lacking Cox-1 showed reduced PGE2 levels in the stomach (30). Thus, the present study also established that the Cox-2/mPGES pathway is indispensable for PGE2 production induced by proinflammatory stimuli, whereas Cox-1/cPGES is required for the basal PGE2 production responsible for maintenance of homeostasis.
There are several reports that PGE2 contributes
to immune suppression and that PGE2 secreted from
activated macrophages in response to proinflammatory stimuli acts on
the macrophages themselves and exhibits an inhibitory function in a
negative feedback loop (21). Addition of exogenous
PGE2 has been shown to reduce LPS-induced IL-6
and TNF- production, but not IL-1 production, in macrophages
(31). Another study showed that PGE2
induces the production of IL-6 (32). Thus, it remains
unclear how PGE2 regulates the production of
inflammatory cytokines. Membrane-associated PGES-mutant mice showed no
LPS-induced elevation of PGE2, providing a good
model to analyze the involvement of PGE2 in the
production of inflammatory cytokines. The LPS-induced production of
TNF- and IL-12 was not altered at various time points, even 24
h after LPS injection in mPGES-mutant mice, indicating that endogenous
PGE2 expressed in response to LPS is not
essential for the regulation of inflammatory cytokine production.
To date, four PGE2 receptors, designated EP1, EP2, EP3, and EP4, have been identified, and their physiological roles demonstrated (1). Mice deficient in EP4 show an increased incidence of patent ductus arteriosus with high neonatal mortality. EP2-deficient female mice consistently deliver fewer pups than their wild-type counterparts due to slightly impaired ovulation and a marked reduction in fertilization. EP3-deficient mice show an impaired febrile response (1). However, mPGES-deficient mice do not show these abnormalities. This may be due to the basally produced PGE2, probably through the Cox-1/cPGES pathway.
In this study we have demonstrated that LPS-induced mPGES expression is essential for LPS-dependent PGE2 production, but not for inflammatory cytokine production. It should be analyzed whether cPGES/p23 is involved in the basal PGE2 production. The generation of mice lacking both mPGES and cPGES should provide new insight into the role of PGE2.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Shizuo Akira, Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail address: sakira{at}biken.osaka-u.ac.jp
3 Abbreviations used in this paper: PLA2, phospholipase A2; PGES, PGE2 synthase; PGHS, PGH synthase; Cox, cyclooxygenase; cPGES, cytosolic PGES; ES, embryonic stem; MAPEG, membrane-associated proteins involved in eicosanoid and glutathione metabolism; MGST1-L1, microsomal glutathione-S-transferase-1-like-1; mPGES, membrane-bound PGES; TLR, Toll-like receptor.
Received for publication December 27, 2001. Accepted for publication April 2, 2002.
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 A. K. Lovgren, L. A. Jania, J. M. Hartney, K. K. Parsons, L. P. Audoly, G. A. FitzGerald, S. L. Tilley, and B. H. Koller COX-2-derived prostacyclin protects against bleomycin-induced pulmonary fibrosis Am J Physiol Lung Cell Mol Physiol, August 1, 2006; 291(2): L144 - L156. [Abstract] [Full Text] [PDF]
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 J. Cong, H.-L. Diao, Y.-C. Zhao, H. Ni, Y.-Q. Yan, and Z.-M. Yang Differential expression and regulation of cylooxygenases, prostaglandin E synthases and prostacyclin synthase in rat uterus during the peri-implantation period Reproduction, January 1, 2006; 131(1): 139 - 151. [Abstract] [Full Text] [PDF]
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S. Herath, D. P. Fischer, D. Werling, E. J. Williams, S. T. Lilly, H. Dobson, C. E. Bryant, and I. M. Sheldon Expression and Function of Toll-Like Receptor 4 in the Endometrial Cells of the Uterus Endocrinology, January 1, 2006; 147(1): 562 - 570. [Abstract] [Full Text] [PDF]
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A. L. Neild, S. Shin, and C. R. Roy Activated Macrophages Infected with Legionella Inhibit T Cells by Means of MyD88-Dependent Production of Prostaglandins J. Immunol., December 15, 2005; 175(12): 8181 - 8190. [Abstract] [Full Text] [PDF]
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 K. Kubota, T. Kubota, D. Kamei, M. Murakami, I. Kudo, T. Aso, and I. Morita Change in prostaglandin E synthases (PGESs) in microsomal PGES-1 knockout mice in a preterm delivery model J. Endocrinol., December 1, 2005; 187(3): 339 - 345. [Abstract] [Full Text] [PDF]
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 S. Chandrasekharan, N. A. Foley, L. Jania, P. Clark, L. P. Audoly, and B. H. Koller Coupling of COX-1 to mPGES1 for prostaglandin E2 biosynthesis in the murine mammary gland J. Lipid Res., December 1, 2005; 46(12): 2636 - 2648. [Abstract] [Full Text] [PDF]
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Y. Shibata, R. A. Henriksen, I. Honda, R. M. Nakamura, and Q. N. Myrvik Splenic PGE2-releasing macrophages regulate Th1 and Th2 immune responses in mice treated with heat-killed BCG J. Leukoc. Biol., December 1, 2005; 78(6): 1281 - 1290. [Abstract] [Full Text] [PDF]
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 W. E. Ackerman IV, J. M. Robinson, and D. A. Kniss Despite Transcriptional and Functional Coordination, Cyclooxygenase-2 and Microsomal Prostaglandin E Synthase-1 Largely Reside in Distinct Lipid Microdomains in WISH Epithelial Cells J. Histochem. Cytochem., November 1, 2005; 53(11): 1391 - 1401. [Abstract] [Full Text] [PDF]
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 F. Masse, S. Guiral, L.-J. Fortin, E. Cauchon, D. Ethier, J. Guay, and C. Brideau An Automated Multistep High-Throughput Screening Assay for the Identification of Lead Inhibitors of the Inducible Enzyme mPGES-1 J Biomol Screen, September 1, 2005; 10(6): 599 - 605. [Abstract] [PDF]
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 A. Sapirstein, H. Saito, S. J. Texel, T. A. Samad, E. O'Leary, and J. V. Bonventre Cytosolic phospholipase A2{alpha} regulates induction of brain cyclooxygenase-2 in a mouse model of inflammation Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1774 - R1782. [Abstract] [Full Text] [PDF]
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A. A. Romanovsky Vioxx, Celebrex, Bextra....Do we have a new target for anti-inflammatory and antipyretic therapy? Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2005; 288(5): R1098 - R1099. [Full Text] [PDF]
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C. E. Trebino, J. D. Eskra, T. S. Wachtmann, J. R. Perez, T. J. Carty, and L. P. Audoly Redirection of Eicosanoid Metabolism in mPGES-1-deficient Macrophages J. Biol. Chem., April 29, 2005; 280(17): 16579 - 16585. [Abstract] [Full Text] [PDF]
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 A. F. Rowley, C. L. Vogan, G. W. Taylor, and A. S. Clare Prostaglandins in non-insectan invertebrates: recent insights and unsolved problems J. Exp. Biol., January 1, 2005; 208(1): 3 - 14. [Abstract] [Full Text] [PDF]
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 G. Giannico, M. Mendez, and M. C. LaPointe Regulation of the membrane-localized prostaglandin E synthases mPGES-1 and mPGES-2 in cardiac myocytes and fibroblasts Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H165 - H174. [Abstract] [Full Text] [PDF]
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C. A. Rouzer, P. J. Kingsley, H. Wang, H. Zhang, J. D. Morrow, S. K. Dey, and L. J. Marnett Cyclooxygenase-1-dependent Prostaglandin Synthesis Modulates Tumor Necrosis Factor-{alpha} Secretion in Lipopolysaccharide-challenged Murine Resident Peritoneal Macrophages J. Biol. Chem., August 13, 2004; 279(33): 34256 - 34268. [Abstract] [Full Text] [PDF]
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D. Kamei, K. Yamakawa, Y. Takegoshi, M. Mikami-Nakanishi, Y. Nakatani, S. Oh-ishi, H. Yasui, Y. Azuma, N. Hirasawa, K. Ohuchi, et al. Reduced Pain Hypersensitivity and Inflammation in Mice Lacking Microsomal Prostaglandin E Synthase-1 J. Biol. Chem., August 6, 2004; 279(32): 33684 - 33695. [Abstract] [Full Text] [PDF]
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A. Bafica, C. A. Scanga, M. Schito, D. Chaussabel, and A. Sher Influence of Coinfecting Pathogens on HIV Expression: Evidence for a Role of Toll-Like Receptors J. Immunol., June 15, 2004; 172(12): 7229 - 7234. [Abstract] [Full Text] [PDF]
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J. Guay, K. Bateman, R. Gordon, J. Mancini, and D. Riendeau Carrageenan-induced Paw Edema in Rat Elicits a Predominant Prostaglandin E2 (PGE2) Response in the Central Nervous System Associated with the Induction of Microsomal PGE2 Synthase-1 J. Biol. Chem., June 4, 2004; 279(23): 24866 - 24872. [Abstract] [Full Text] [PDF]
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L. Boulet, M. Ouellet, K. P. Bateman, D. Ethier, M. D. Percival, D. Riendeau, J. A. Mancini, and N. Methot Deletion of Microsomal Prostaglandin E2 (PGE2) Synthase-1 Reduces Inducible and Basal PGE2 Production and Alters the Gastric Prostanoid Profile J. Biol. Chem., May 28, 2004; 279(22): 23229 - 23237. [Abstract] [Full Text] [PDF]
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S. Cheng, H. Afif, J. Martel-Pelletier, J.-P. Pelletier, X. Li, K. Farrajota, M. Lavigne, and H. Fahmi Activation of Peroxisome Proliferator-activated Receptor {gamma} Inhibits Interleukin-1{beta}-induced Membrane-associated Prostaglandin E2 Synthase-1 Expression in Human Synovial Fibroblasts by Interfering with Egr-1 J. Biol. Chem., May 21, 2004; 279(21): 22057 - 22065. [Abstract] [Full Text] [PDF]
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H.-K. Lim, Y.-A. Choi, W. Park, T. Lee, S. H. Ryu, S.-Y. Kim, J.-R. Kim, J.-H. Kim, and S.-H. Baek Phosphatidic Acid Regulates Systemic Inflammatory Responses by Modulating the Akt-Mammalian Target of Rapamycin-p70 S6 Kinase 1 Pathway J. Biol. Chem., November 14, 2003; 278(46): 45117 - 45127. [Abstract] [Full Text] [PDF]
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M. Murakami, K. Nakashima, D. Kamei, S. Masuda, Y. Ishikawa, T. Ishii, Y. Ohmiya, K. Watanabe, and I. Kudo Cellular Prostaglandin E2 Production by Membrane-bound Prostaglandin E Synthase-2 via Both Cyclooxygenases-1 and -2 J. Biol. Chem., September 26, 2003; 278(39): 37937 - 37947. [Abstract] [Full Text] [PDF]
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C. N. Serhan and B. Levy Success of prostaglandin E2 in structure-function is a challenge for structure-based therapeutics PNAS, July 22, 2003; 100(15): 8609 - 8611. [Full Text] [PDF]
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C. E. Trebino, J. L. Stock, C. P. Gibbons, B. M. Naiman, T. S. Wachtmann, J. P. Umland, K. Pandher, J.-M. Lapointe, S. Saha, M. L. Roach, et al. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase PNAS, July 22, 2003; 100(15): 9044 - 9049. [Abstract] [Full Text] [PDF]
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D. Kamei, M. Murakami, Y. Nakatani, Y. Ishikawa, T. Ishii, and I. Kudo Potential Role of Microsomal Prostaglandin E Synthase-1 in Tumorigenesis J. Biol. Chem., May 23, 2003; 278(21): 19396 - 19405. [Abstract] [Full Text] [PDF]
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C. Miyaura, M. Inada, C. Matsumoto, T. Ohshiba, N. Uozumi, T. Shimizu, and A. Ito An Essential Role of Cytosolic Phospholipase A2{alpha} in Prostaglandin E2-mediated Bone Resorption Associated with Inflammation J. Exp. Med., May 19, 2003; 197(10): 1303 - 1310. [Abstract] [Full Text] [PDF]
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D. Claveau, M. Sirinyan, J. Guay, R. Gordon, C.-C. Chan, Y. Bureau, D. Riendeau, and J. A. Mancini Microsomal Prostaglandin E Synthase-1 Is a Major Terminal Synthase That Is Selectively Up-Regulated During Cyclooxygenase-2-Dependent Prostaglandin E2 Production in the Rat Adjuvant-Induced Arthritis Model J. Immunol., May 1, 2003; 170(9): 4738 - 4744. [Abstract] [Full Text] [PDF]
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