peran Cyclooxigenase 2 dan Prostaglandin E2 pada penyakit periodontal

The roles of cyclooxygenase-2and prostaglandin E2 inperiodontal disease

KAZUYUKI NOGUCHI & ISAO ISHIKAWA

Prostanoids, including prostaglandins and throm-

boxane, have a variety of roles in physiological and

pathological conditions including inflammation,

immunological function, ovulation, implantation,

cardiovascular disease, and tumorigenesis (153).

Prostanoids contribute to the signs and symptoms of

acute and chronic inflammation including pain,

fever, swelling, and vasodilatation. The physiological

importance of prostanoids is highlighted by the use

of the cyclooxygenase-inhibiting non-steroidal anti-

inflammatory drugs in the clinical treatment of dis-

orders. In response to various stimuli, arachidonic

acid released from membrane phospholipids is

metabolized to prostaglandins and thromboxane by

cyclooxygenase. In the early 1990s, two isoforms of

cyclooxygenase, cyclooxygenase-1 and cyclooxyge-

nase-2, were identified (62, 63, 154). Generally,

whereas cyclooxygenase-1 is constitutively expressed

in many tissues and supports the prostaglandin bio-

synthesis required for maintaining organ and tissue

homeostasis, cyclooxygenase-2 is induced after sti-

mulation with proinflammatory molecules including

interleukin-1, tumor necrosis factor-a, and lipopoly-saccharide, and is up-regulated during inflammation.

Traditional non-steroidal anti-inflammatory drugs

such as aspirin, naproxen, and indomethacin inhibit

both cyclooxygenase-1 and cyclooxygenase-2 activ-

ities and possess adverse side effects that include

gastrointestinal toxicity. Selective cyclooxygenase-2

inhibitors have been developed with the expectation

of safer and fewer adverse side effects; some of them

have already been used for the clinical treatment of

pain associated with osteoarthritis, rheumatoid

arthritis, and menstruation. Furthermore, recent

molecular and pharmacological analysis has dem-

onstrated that prostanoids exert their biological

actions via specific prostanoid receptors on target

cells, suggesting possible mechanisms of their com-

plicated effects.

Microbial organisms in dental plaque are consid-

ered as primary pathogens of periodontal disease.

However, the response of the host to the pathogens,

which induces the production of inflammatory

molecules including cytokines and prostanoids, is

involved in the initiation and progression of perio-

dontal disease (111). Numerous studies have indica-

ted that prostanoids, in particular prostaglandin E2,

are involved in the pathogenesis of periodontal dis-

ease. Elevated prostaglandin E2 levels are detected in

the gingiva and gingival crevicular fluid of patients

with periodontal diseases, compared to periodontally

healthy subjects (24, 110). In 1974, Goodson et al. (34)

reported a 10-fold increase of prostaglandin E2 levels

in inflamed gingival tissue, compared with healthy

gingival tissue. Other researchers also showed that

prostaglandin E2 levels are elevated in periodontal

tissue in patients with gingivitis and periodontitis (24,

107). Offenbacher at al. (108) demonstrated that

prostaglandin E2 levels in gingival crevicular fluid of

patients exhibiting periodontal diseases are signifi-

cantly higher than those in periodontally healthy

subjects, and furthermore that prostaglandin E2concentrations in gingival crevicular fluid are effect-

ive for predicting periodontitis progression, i.e.

attachment loss, with a high degree of sensitivity and

specificity (0.76 and 0.96, respectively). Roberts et al.

(116) showed that immunization of Macaca fascicu-

laris monkeys with formalin-killed Porphyromonas

gingivalis resulted in less bone loss than in non-

immunized control animals in the ligature-induced

periodontitis model and that there was a significant

correlation between prostaglandin E2 levels in gingi-

val crevicular fluid and decreased bone scores. Pre-

vious studies have demonstrated that traditional

85

Periodontology 2000, Vol. 43, 2007, 85101

Printed in Singapore. All rights reserved

2007 The Authors.Journal compilation 2007 Blackwell Munksgaard

PERIODONTOLOGY 2000

non-steroidal anti-inflammatory drugs including

indomethacin (105, 147, 148), flurbiprofen (146, 147,

149), ibuprofen (109, 150), naproxen (44, 109), and

meclofenamic acid (60), piroxicam (45), and keto-

profen (66), reduce the progression of periodontal

diseases in animal models. In humans, cross-sec-

tional and cohort studies indicated that subjects

taking non-steroidal anti-inflammatory drugs for the

treatment of arthritis or ankylosing spondylitis had

lower gingival index scores and shallower periodontal

pocket depths as compared with controls taking no

non-steroidal anti-inflammatory drugs (143). Fur-

thermore, Williams et al. (151) compared the mean

rate of alveolar bone loss in chronic periodontitis

patients administered flurbiprofen 50 mg twice daily

or placebo twice daily over a 2-year period and

demonstrated significantly lower bone loss in flurbi-

profen-taking patients compared with patients taking

placebo. Naproxen and meclofenamate sodium are

effective even for the treatment of rapidly progressive

periodontitis (aggressive periodontitis) (52, 114).

Recent accumulating data have shown that cyclo-

oxygenase-2 expression is enhanced in human

inflamed gingival tissues and that cyclooxygenase-2 is

responsible forprostaglandinE2production in thecells

stimulated with proinflammatory molecules, sug-

gesting that cyclooxygenase-2 plays a crucial role for

prostaglandin E2 production in periodontal disease.

It is of much interest how cyclooxygenase-2 and

prostaglandin E2 expression are regulated and what

roles they play in periodontal disease. In this review,

we will highlight and discuss the roles of cyclooxy-

genase-2, prostaglandin E2, and its receptors in per-

iodontal disease.

Prostanoid synthesis

Prostanoids are ubiquitous bioactive lipid molecules

derived from the unsaturated 20-carbon fatty acid

arachidonic acid. Prostanoid synthesis is carried out

in three steps: (i) the mobilization of a fatty

acid substrate, typically arachidonic acid, from

membranous phospholipids, through the action of

phospholipase A2, (ii) the formation of prostaglandin

H2 from arachidonic acid by cyclooxygenase, and

(iii) the conversion of prostaglandin H2 to specific

prostanoids by the action of various prostaglandin

synthases, generating five primary bioactive prosta-

noids including prostaglandin D2, prostaglandin E2,

prostaglandin F2a, prostaglandin I2 (prostacyclin),

and thromboxane A2 (Fig. 1). These prostanoids act

within tissues and cells via specific G-protein-cou-

pled prostanoid receptors, a family of rhodopsin-like

seven transmembrane spanning receptors. They are

designated EP for prostaglandin E2 receptors and FP,

DP, IP, and TP for prostaglandin F2a, prostaglandin

D2, prostaglandin I2 and thromboxane A2 receptors,

respectively (19, 87).

Since 1971, when Vane (140) demonstrated that the

mechanism for the anti-inflammatory effects of non-

steroidal anti-inflammatory drugs is dependent on

the inhibition of prostaglandin synthesis, numerous

studies have focused on cyclooxygenase to develop

anti-inflammatory drugs. In the early 1990s, it was

revealed that there are two types of cyclooxygenase,

cyclooxygenase-1 and cyclooxygenase-2 (62, 63, 154).

Recently, it has been suggested that there is another

cyclooxygenase protein formed as a splice variant of

Fig. 1. Pathway of prostanoid syn-

thesis. COX-1, cyclooxygenase-1;

COX-2, cyclooxygenase-2; PG, pros-

taglandin; PGH2, prostaglandin H2;

PGI2, prostaglandin I2; PGD2, pros-

taglandin D2; PGE2, prostaglandin

E2; PGF2a, prostaglandin F2a; TXA2,

thromboxane A2.

86

Noguchi & Ishikawa

cyclooxygenase-1, named cyclooxygenase-3, the

functions of which are still unknown (14). Table 1

shows a comparison of the properties of cyclooxy-

genase-1 and cyclooxygenase-2. The amino acid

sequence homology between cyclooxygenase-1 and

cyclooxygenase-2 is approximately 60% for the

human enzymes. Whereas the human cyclooxyge-

nase-1 promoter region lacks a canonical TATA or

CAAT box, the human cyclooxygenase-2 promoter

region has potential transcriptional regulatory ele-

ments including a TATA box, and nuclear factor-IL-6

motif, two AP-2 sites, three Sp1 sites, two nuclear

factor-jB sites, a cyclic AMP-responsive elementmotif, and an E-box (134). Although exceptions exist,

cyclooxygenase-1 is considered to be constitutively

expressed in many tissues and cells, while the

expression of cyclooxygenase-2 is inducible, partic-

ularly in response to inflammatory cytokines and

stimuli including interleukin-1, tumor necrosis

factor-a and lipopolysaccharide, and growth factors(41, 53, 65, 106). High levels of cyclooxygenase-1 are

expressed in platelets, stomach, and kidney, and

cyclooxygenase-1-derived prostanoids from the tis-

sues are involved in platelet aggregation, gastroin-

testinal homeostasis, and renal perfusion. On the

other hand, cyclooxygenase-2 expression is associ-

ated with the biosynthesis of the large amounts of

prostanoids observed during pathological conditions

such as inflammation and cancer progression. Based

on these observations, there is a hypothesis that

unwanted side effects of traditional non-steroidal

anti-inflammatory drugs, such as damage to gastric

mucosa and gastrointestinal bleeding, result from

inhibition of cyclooxygenase-1, whereas therapeutic

anti-inflammatory and anti-tumor effects involve

inhibition of cyclooxygenase-2 (141). It has been

indicated that the combined inhibition of both

cyclooxygenase-1 and cyclooxygenase-2 might be

responsible for the development of gastric ulcers

following the administration of non-steroidal anti-

inflammatory drugs (144). Therefore, highly selective

cyclooxygenase-2 inhibitors have been developed as

useful anti-inflammatory agents with lower gastro-

intestinal toxicity. Selective inhibitors of cyclooxyge-

nase-2 are as effective as traditional non-steroidal

anti-inflammatory drugs in the treatment of pain and

inflammation, but are less prone to cause gastric

ulceration. It has also been reported that cyclooxy-

genase-2 inhibitors are effective for relief of post-

operative dental pain (35, 70, 83). There are selective

cyclooxygenase-2 inhibitors including NS-398,

nimesulide, etodolac, meloxicam, celecoxib, rofec-

oxib, etoricoxib, paracoxib, valdecoxib, and lumirac-

oxib. Some of them are available in the clinic for the

treatment of osteoarthritis and rheumatoid arthritis.

Cyclooxygenase-2 is also observed in some tissues

such as vascular endothelium, kidney, or brain under

normal conditions, suggesting the involvement of cy-

clooxygenase-2 in the regulation of physiological pro-

cesses (27, 28). Very recently, it has been reported that

rofecoxib increases the risk of heart attack and sudden

cardiacdeathafter a longperiodof intake, compared to

a traditional non-steroidal anti-inflammatory drug,

naproxen (55). This finding raises the question of

whether the cardiovascular effects of rofecoxib are an

effect applicable to all cyclooxygenase-2 inhibitors. It

Table 1. Comparison of human cyclooxygenase-1 and cyclooxygenase-2 properties

Cyclooxygenase-1 Cyclooxygenase-2

Enzyme expression Constitutive Inducible

Character of gene House-keeping gene Immediate early gene

Locus 9q32q33.3 1q25.2q25.3

Size of gene 22 kb 8.3 kb

Number of amino acids 576 amino acids 604 amino acids

5-flanking region No TATA, GC rich, Sp1 Nuclear factor-jB, nuclear factor-IL-6, cyclicAMP-response element, E-box, TATA box

Size of RNA 2.8 kb 4.6 kb

Expressing cells Most cells Not detected in normal conditions.

Increased in fibroblasts, monocytes, osteoblasts by IL-1,

tumor necrosis factor a and lipopolysaccharide et al.

Glucocorticoid effect No or slight effect of transcription Inhibition of transcription

87

Roles of cyclooxygenase-2 and prostaglandin E2

has been indicated that cyclooxygenase-1 can be

enhanced in some cell types (82). Thus, the capacity

for cyclooxygenase-1 to regulate the inflammatory

response should not be overlooked.

Prostaglandin E2 receptors

Prostaglandin E2 is a major product of cyclooxyge-

nase-initiated arachidonic acid metabolism. Prosta-

glandin E2 has multiple and at times apparently

opposing functional effects including fever, pain,

vasodilatation, bone resorption, and formation, on a

given target tissue and cell (50, 153). The diverse ef-

fects of prostaglandin E2 are now explained by evi-

dence for the existence of multiple prostaglandin E2receptors (EP receptors) on plasma membranes.

Pharmacological analysis and molecular cloning have

revealed the existence of four EP receptor subtypes,

each coded by distinct genes. These receptors are

designated EP1, EP2, EP3, and EP4. The binding

affinities of prostaglandin E2 to the EP receptors have

the following rank order: EP3 > EP4 >> EP2 > EP1,

with Kd values ranging 100-fold from 0.33 to 25 nM (1).

The EP1 receptor was originally described as a

smooth muscle constrictor. The cloned human EP1receptor cDNA encodes a 402-amino-acid polypep-

tide (31). Activation of the EP1 receptor leads to

signals via inositol trisphosphate generation and

increased intracellular Ca2+ levels. The human EP2receptor cDNA encodes a 358-amino-acid poly-

peptide (115). Activation of the EP2 receptor leads to

an increase in cyclic AMP levels. EP2 receptors are

selectively activated by butaprost and butaprost

activation is considered diagnostic for their charac-

terization. EP3 receptors have multiple splice variants

generated by alternative splicing of the C-terminal

tail. In humans at least eight EP3 receptor isoforms

have been identified (61), and multiple splice vari-

ants exist for other species including mouse, rabbit,

and cow. Originally, the EP3 receptor was described

as coupling to a Gi-type G protein leading to inhi-

bition of intracellular cyclic AMP (130), but subse-

quently it was shown that individual splice variants

could also couple to enhancement of cyclic AMP and

inositol trisphosphate generation (46, 86). It is true

that important functional differences exist between

the EP3 receptor splice variants in cell culture sys-

tems, but the physiological significance of these

different C-terminal splice variants remains unclear.

The EP4 receptor couples to a Gs-type G protein

leading to stimulation of adenylyl cyclase and in-

creased intracellular cyclic AMP levels. The human

EP4 receptor cDNA encodes a 488-amino acid poly-

peptide with a predicted molecular mass of 53 kDa(4). Before 1995, this receptor cDNA was generally

referred to as the EP2 receptor (91). Functional dif-

ferences in EP2 versus EP4 receptor signaling may

also arise from differential agonist-induced desensi-

tization and internalization. Compared to the EP2receptor, the EP4 receptor has a much longer C-ter-

minal tail that is required for rapid agonist-induced

desensitization (3) and undergoes agonist-induced

internalization (21).

Recently, the expression of functional EP receptors

(EP1, EP3, and EP4) on the nuclear membranes of

cells has been documented (6, 7). Further studies are

necessary to determine the processes that govern the

expression and function of the nuclear-localized

receptors.

Involvement of cyclooxygenase-2in prostaglandin E2 production inperiodontal disease

Cavanaugh et al. (13) first performed the immunoh-

istochemical analysis of cyclooxygenase-2 protein

expression in inflamed gingival tissues. They found

that cyclooxygenase-1 and cyclooxygenase-2 proteins

were expressed in fibroblasts, gingival epithelial cells,

endothelial cells, and inflammatory mononuclear

cells.Weexamined theexpressionof cyclooxygenase-1

and cyclooxygenase-2 proteins in clinically healthy

and inflamed human gingiva. In both types of

gingiva, cyclooxygenase-1-immunoreactive cells were

detected in subepithelial connective tissue including

fibroblasts and endothelial cells and some gingival

epithelial cells were slightly immunopositive for

cyclooxygenase-1 (Fig. 2A,C). In inflamed gingiva,

inflammatory cells were also immunopositive for

cyclooxygenase-1. However, cyclooxygenase-2 pro-

tein was detected in fibroblasts, gingival epithelial

cells, endothelial cells, and inflammatory cells in

inflamed gingiva, whereas in clinically healthy gingiva,

it was detected at low levels in only gingival epithelial

cells andfibroblasts (Fig. 2B,D). Zhang et al. (161) have

demonstrated by quantitative polymerase chain

reaction and Western blot that cyclooxygenase-2

messenger ribonucleic acid and protein levels are

elevated in inflamed gingival tissues from periodonti-

tis patients compared with in uninflamed tissues from

healthy subjects. Furthermore, Morton & Dongari-

Bagtzoglou (84) have reported that the levels of cy-

clooxygenase-2 protein are higher in more inflamed

gingival tissues. Recently, Miyauchi et al. (79) have

88

Noguchi & Ishikawa

demonstrated that cyclooxygenase-2 expression is

induced in cementoblasts after application of lipo-

polysaccharide to rat periodontal tissues.

In vitro studies have shown that cyclooxygenase-2

plays an important role in producing prostaglandins

in various cells stimulated with proinflammatory

stimuli. Cultured monocytes/macrophages produce

prostaglandin E2 in response to lipopolysaccharides

derived from periodontopathic bacteria including

Actinobacillus actinomycetemcomitans and P. gingi-

valis (97). This prostaglandin E2 production is

completely inhibited by NS-398, a specific cyclo-

oxygenase-2 inhibitor, and cyclooxygenase-2 mes-

senger ribonucleic acid and protein expression is

induced, whereas cyclooxygenase-1 messenger ribo-

nucleic acid and protein expression is not changed,

which suggests that human monocytes produce

prostaglandin E2 via cyclooxygenase-2 in response to

the lipopolysaccharides of periodontopathic bacteria.

Prostaglandin E2 production was enhanced in

lipopolysaccharide-stimulated peripheral blood

monocytes from patients with localized aggressive

periodontitis, compared with healthy subjects (125).

Li et al. (68) performed genetic linkage analysis with

four multigenerational families exhibiting a localized

aggressive periodontitis phenotype, and showed that

a localized aggressive periodontitis locus is located

between D1S196 and D1S556. Furthermore, they

examined the DNA sequence of cyclooxygenase-2

because cyclooxygenase-2 is located between D1S196

and D1S556, but no mutation of cyclooxygenase-2

was identified in the patients.

Interleukin-1b is a potent stimulator of prosta-glandin production via cyclooxygenase-2 in human

gingival fibroblasts (48, 98, 157). Interleukin-1b-challenged human gingival fibroblasts induce cyclo-

oxygenase-2 expression via tyrosine kinase pathways

(159). Tumor necrosis factor-a is a less potent sti-mulator of prostaglandin E2 production compared

with interleukin-1, but tumor necrosis factor-a andinterleukin-1 synergistically enhance prostaglandin

E2 production (158). Human gingival fibroblasts

challenged with periodontopathic bacteria lipopoly-

saccharides produce prostaglandin E2 via cyclo-

oxygenase-2 induction, which is regulated by tyrosine

kinases (93). Recently, it has been shown that an

erbium:yttriumaluminumgarnet (Er:YAG) laser

induces cyclooxygenase-2 expression to produce

Fig. 2. Immunohistochemical staining of cyclooxygenase-

1 (COX-1) and cyclooxygenase-2 (COX-2) proteins in

clinically healthy and inflamed human gingiva. In both

gingiva, COX-1-immunoreactive cells were detected in

subepithelial connective tissue including fibroblasts and

endothelial cells and some gingival epithelial cells were

slightly immunopositive for COX-1 (A, C). In inflamed

gingiva, inflammatory cells were also immunopositive for

COX-1. However, COX-2 protein was detected in fibro-

blasts, gingival epithelial cells, endothelial cells, and

inflammatory cells in inflamed gingiva, whereas in

clinically healthy gingiva, it was slightly detected in gin-

gival epithelial cells and fibroblasts (B, D). Magnification

400.

89


prostaglandin E2 in a laser-energy-dependent man-

ner, suggesting that cyclooxygenase-2-dependent

prostaglandin E2 by Er:YAG laser irradiation may play

an important role in the acceleration of gingival

fibroblast proliferation (113). However, Ga-Al-As

diode low-level laser irradiation inhibits Campylo-

bacter rectus lipopolysaccharide-induced prostaglan-

din E2 in human gingival fibroblasts through a

reduction of cyclooxygenase-2 messenger ribonucleic

acid levels (122). Smoking is a serious risk factor for

periodontal diseases. Nicotine can induce cyclo-

oxygenase-2 messenger ribonucleic acid and protein

expression in human gingival fibroblasts (15).

In human periodontal ligament cells, it has been

reported that interleukin-1a and interleukin-1bpotently induce prostaglandin E2 via cyclooxygenase-

2 induction (39, 95, 96). Mechanical stress also

induces cyclooxygenase-2 (126). Tumor necrosis

factor-a alone is a weak stimulator of prostaglandinE2 production in periodontal ligament cells. How-

ever, tumor necrosis factor-a synergistically producesprostaglandin E2 with interleukin-1, like human

gingival fibroblasts (K. Noguchi, unpublished data).

In gingival epithelial cells, our group showed that

serum stimulation generated prostaglandin E2 via

cyclooxygenase-2 messenger ribonucleic acid and

protein induction, while interleukin-1b, tumor nec-rosis factor-a, and lipopolysaccharide could not in-duce prostaglandin E2 production (99). In the study,

it was not examined whether cyclooxygenase-2

expression was induced in response to interleukin-

1b, tumor necrosis factor-a and lipopolysaccharide.Using oral squamous carcinoma cell lines, it was

demonstrated that tumor necrosis factor-a andinterleukin-1b induced cyclooxygenase-2 messengerribonucleic acid and protein (161). Actinobacillus

actinomycetemcomitans was reported to induce

cyclooxygenase-2 expression to produce prostaglan-

din E2 in gingival epithelial cells (102). It has been

shown that a fourfold increase of cyclooxygenase-2

messenger ribonucleic acid levels is observed in the

oral mucosa of active smokers vs. never smokers and

that tobacco smoke stimulates cyclooxygenase-2

transcription, resulting in cyclooxygenase-2 expres-

sion and prostaglandin E2 synthesis in oral epithelial

cells (81). Thus, tobacco smoke may also induce the

production of cyclooxygenase-2 expression and

prostaglandin E2 in gingival epithelial cells. It is

suggested that gingival epithelial cells may be a

source of proinflammatory cytokines including

interleukin-1 (123). Therefore, gingival epithelial cells

may be important cells in the regulation of inflam-

matory responses.

There are several endogenous inhibitors to sup-

press prostaglandin production in vivo. Glucocorti-

coid can down-regulate cyclooxygenase-2 expression

to reduce prostaglandin production (74). In addition

to glucocorticoid, interleukin-4, interleukin-10, and

interleukin-13 are well known as anti-inflammatory

cytokines. The cytokines can inhibit the production

of proinflammatory cytokines such as interleukin-1,

interleukin-6, interleukin-8, and tumor necrosis

factor-a by monocytes (16, 38) and suppress boneresorption (145). Interleukin-4, interleukin-10, and

interleukin-13 can inhibit prostaglandin production

via down-regulation of cyclooxygenase-2 expression

in human monocytes and neutrophils (25, 90, 89). In

human gingival fibroblasts and periodontal ligament

cells, interleukin-4 decreased interleukin-1-induced

prostaglandin production via inhibition of cyclo-

oxygenase-2 expression with no effect on cyclooxy-

genase-1 expression. Interleukin-13 also inhibits

interleukin-1-induced prostaglandin production via

inhibition of cyclooxygenase-2 expression although it

is less potent compared to interleukin-4 (unpub-

lished data). Recently, it has been shown that

interleukin-4 receptor and interleukin-13 receptor

(interleukin-13 receptor a1 chain) are expressed inhuman gingival fibroblasts (64). Interleukin-4, inter-

leukin-10, and interleukin-13 are detected in

inflamed periodontal tissues. Furthermore, inter-

feron-c, a Th1 cytokine, also decreases interleukin-1-elicited prostaglandin E2 production in human

gingival fibroblasts and human periodontal liga-

ment cells (39, 95). Hayashi et al. (39) reported that

interferon-c inhibited interleukin-1-induced cyclo-oxygenase-2 expression, but we could not find the

inhibitory effect of interferon-c on cyclooxygenase-2expression (95). It is plausible that in periodontal

lesions there are inhibitory systems to regulate

prostaglandin production.

From these results, it is very likely that cyclooxyg-

enase-2 plays a crucial role in producing prosta-

glandin production in periodontal lesions. As shown

in Fig. 3, there may be stimulatory and inhibitory

systems to regulate prostaglandin production by cell

cell interaction in periodontal lesions.

Effects of specific cyclooxygenase-2inhibitors on the progression ofperiodontal disease

As described above, traditional non-steroidal anti-

inflammatory drugs effectively inhibit the progres-

90

Noguchi & Ishikawa

sion of periodontal diseases. It is of interest whether

selective cyclooxygenase-2 inhibitors are effective for

the treatment of periodontal disease (Table 2). In

2000, Bezerra et al. (5) showed that meloxicam, a

selective cyclooxygenase-2 inhibitor, reduced bone

resorption by 50%, as did indomethacin, in rats

with ligature-induced periodontitis; the meloxicam

induced less gastric damage than indomethacin.

They also found that meloxicam and indomethacin

inhibited neutrophilia and lymphomonocytosis.

Fig. 3. Hypothetical regulatory mechanism of cyclooxyg-

enase-2 (COX-2) expression and prostaglandin E2 (PGE2)

production through cellcell interaction in periodontal

lesions. As a stimulatory mechanism for PGE2 production

in periodontal lesions, periodontopathic pathogens may

directly activate monocytes/macrophages (M/ and fibro-blasts to induce COX-2 expression, resulting in PGE2production, or may stimulate monocytes/macrophages

and gingival epithelial cells to produce proinflammatory

cytokines including interleukin-1 (IL-1) and tumor nec-

rosis factor-a (TNF-a), which induce COX-2 protein inmonocyte/macrophages and fibroblasts to produce PGE2.

In some settings, anti-inflammatory cytokines including

interleukin-4 (IL-4), IL-10, and IL-13 may be involved in

inhibiting PGE2 overproduction by down-regulating COX-

2 expression.

Table 2. In vivo studies of effects of cyclooxygenase-2 inhibitors on progression of periodontitis

Reference Methods/results

Bezerra et al. (5) The effect of indomethacin and meloxicam on ligature-induced periodontitis in rats.

Indomethacin and meloxicam similarly prevented alveolar bone loss.

Lohinai et al. (69) The effect of NS-398 on ligature-induced periodontitis in rats.

NS-398 significantly reduced plasma extravasation and alveolar bone resorption.

Holzhausen et al. (42) The effect of celecoxib on ligature-induced periodontitis in rats.

Celecoxib inhibited bone loss in a shorter period than 30 days.

Buduneli et al. (10) The effect of meloxicam on matrix metalloproteinase-8 levels of gingival crevicular fluid

in chronic periodontitis patients following the initial preparation. Meloxicam showed

a tendency to reduce gingival crevice fluid matrix metalloproteinse-8 levels within

the first 10 days.

Vardar et al. (142) The effect of nimesulide on gingival tissue levels of prostaglandin E2 and prostaglandin

F2a in chronic periodontitis patients. On day 10, prostaglandin F2a levels significantly

decreased with an insignificant effect on prostaglandin E2 levels

Gurgel et al. (36) The effect of meloxicam on bone loss in ligature-induced periodontitis in rats and its

post-treatment effect after administration withdrawal. Meloxicam reduced bone loss.

No remaining effect was expected after its withdrawal.

91


Lohinai et al. (69) also demonstrated that NS-398

reduced the plasma extravasation and alveolar bone

resorption in rats with ligature-induced periodontitis.

From these findings, the possibility was indicated

that in vivo cyclooxygenase-2 was involved in

inflammation and bone resorption in periodontitis.

However, Holzhausen et al. (42) showed that celec-

oxib, a selective cyclooxygenase-2 inhibitor, caused a

reduction in bone loss after 18 days of administration

in rats with ligature-induced periodontitis, whereas

no significant difference was observed between con-

trol and tested groups after 30 days. Buduneli et al.

(10) demonstrated in chronic periodontitis patients

that meloxicam had a tendency to reduce gingival

crevicular fluid collagenase-2 (matrix metalloprote-

inase-8) levels shortly after the initial phase of

periodontal therapy. Importantly, with both cyclo-

oxygenase-2 inhibitors and traditional non-steroidal

anti-inflammatory drugs, after drug withdrawal there

is no remaining effect, i.e. the inhibitory effects can

be expected only as long as the drugs are being

administered (36, 152).

Vardar et al. (142) examined the effect of nimesu-

lide, a relatively selective cyclooxygenase-2 inhibitor,

and naproxen, a non-selective cyclooxygenase-1/-2

inhibitor, on gingival tissue levels of prostaglandin E2and prostaglandin F2a in chronic periodontitis tissues

for a short period of 10 days, and showed that

nimesulide might have an additional inhibitory effect

on gingival tissue prostaglandin F2a levels in the first

week following the initial phase of periodontal ther-

apy and that nimesulide had an insignificant effect

on reducing prostaglandin E2 levels in gingival tissue.

Long-term studies may provide further support for

the adjunctive use of selective cyclooxygenase-2

inhibitors in the treatment of periodontal disease.

Effects of prostaglandin E2 onimmune and inflammatoryresponses

It has been suggested that prostaglandin E2 plays an

important role at multiple levels within the immune

system. Prostaglandin E2 induces T-cell proliferation

via inhibition of polyamine synthesis, intracellular

calcium release or the activity of p59 protein tyrosine

kinase (17, 18, 117). Prostaglandin E2 causes apop-

tosis of T cells, depending on the maturation state of

the cells.

Interleukin-12 plays critical roles in the induction

of T helper type 1 (Th1) responses by regulating the

differentiation of Th0 cells to Th1 cells and is believed

to be a key cytokine in modulating the balance

between Th1 and Th2 responses. Prostaglandin E2 is

thought to shift the balance in favor of a Th2

response, in part by EP4-receptor-mediated inhibi-

tion of interleukin-12 production by monocytes/

macrophages (88) as well as by acting directly on T

cells to suppress the production of interleukin-12 and

interferon-c (56, 58). Which of the Th1 or Th2responses is dominant in periodontal lesions is still a

matter of controversy (32). Some groups have

reported that Th1 cytokine mRNA, including inter-

feron-c, was prominently expressed in diseased gin-gival tissues (23, 30) and other groups have shown a

predominance of Th2 responses such as decreased

interleukin-2 levels and increased interleukin-4 and

interleukin-5 levels in periodontal lesions (2, 137).

Recently, Fokkemaet al. (29) have reported a reduction

of interleukin-12p70 production, with prostaglandin

E2 levels elevated, in lipopolysaccharide-stimulated

whole blood cell cultures from periodontitis patients

compared with those from periodontally healthy

subjects. Iwasaki et al. (49) showed that prostaglandin

E2 down-regulates interleukin-12 production through

EP4 receptors in human monocytes stimulated with

lipopolysaccharide from A. actinomycetemcomitans

and interferon-c. Therefore, it is very likely thatincreased prostaglandin E2 production causes

decreased interleukin-12 generation in periodontal

lesions, leading to a predominance of Th2 responses.

Further in vivo studies are needed to elucidate the

relationships between prostaglandin E2 and Th1/Th2

responses in periodontal lesions.

Prostaglandin E2 stimulates the production of

IgG1 and IgE in lipolysaccharide- and interleukin-

4-stimulated B cells in cyclic AMP-dependent

mechanisms (26). It was shown that low doses of

prostaglandin E2 and interleukin-4 synergistically

enhance immunoglobulin G production by gingival

mononuclear cells (37). Interestingly, it was reported

that prostaglandin E2 was responsible for the

increased immunoglobulin G2 production that is

observed in juvenile patients with localized perio-

dontitis (47) and that the prostaglandin E2 effect may

be ascribed to increased interferon-c production(135).

Monocytes/macrophages can produce a variety of

proinflammatory cytokines. Shinomiya et al. (127)

demonstrated using murine peritoneal macrophages

stimulated with zymosan that prostaglandin E2caused down-regulation of the zymosan-induced

tumor necrosis factor-a production, but up-regula-tion on the interleukin-10 production via EP2 and EP4

92

Noguchi & Ishikawa

receptors. Prostaglandin E2 down-regulates lipo-

polysaccharide-induced tumor necrosis factor-ageneration in monocytes/macrophages (76). We

investigated the effect of prostaglandin E2 on

A. actinomycetemcomitans lipopolysaccharide-in-

duced tumor necrosis factor-a production in humanmonocytes. As shown in Fig. 4, prostaglandin E2inhibited A. actinomycetemcomitans lipopolysaccha-

ride-induced tumor necrosis factor-a production in adose-dependent manner. EP4 and to a lesser extent

EP2 receptors were involved in the inhibition of

tumor necrosis factor-a production. Prostaglandin E2suppresses production of chemokines including

interleukin-8, monocyte chemoattractant protein-1,

and macrophage inflammatory protein-1 via EP4receptors in human macrophages stimulated with

lipopolysaccharide (132).

Intercellular adhesion molecule-1 is a glycosylated

membrane protein, which is a member of the

immunoglobulin superfamily. It functions as a ligand

for the b2-integrins lymphocyte function-associatedantigen-1 (CD11a/CD18) and Mac-1 (CD11b/CD18),

and plays pivotal roles in a wide range of immune

responses (22). Several studies have suggested that

intercellular adhesion molecule-1 is an important

molecule in mediating cellcell interaction such

as that between lymphocytes and gingival fibro-

blasts (85). It was shown that prostaglandin E2down-regulated interleukin-1b-, tumor necrosis fac-tor-a- and lipopolysaccharide-induced intercellularadhesion molecule-1 expression via EP2/EP4 recep-

tors in human gingival fibroblasts (94, 98, 100).

Interleukin-6 is a pleiotropic cytokine, which

induces B-cell activation and osteoclast formation.

Interleukin-1 can induce interleukin-6 production in

human gingival fibroblasts. Prostaglandin E2 sup-

presses interleukin-1-induced interleukin-6 produc-

tion in human gingival fibroblasts derived from

periodontally healthy subjects, but increases inter-

leukin-1-induced interleukin-6 production in human

gingival fibroblasts derived from periodontitis

patients (20, 133), To explain the differential

regulation by prostaglandin E2, we showed that EP1receptor activation causes an increase in interleukin-

1-induced interleukin-6 production while EP2/EP4receptor activation leads to a decrease (101). The

differential regulation of matrix metalloproteinase-3

production by prostaglandin E2 in healthy subjects

and periodontitis patients was also reported (118).

Therefore, the difference of expression and functions

of EP receptors may be involved in the regulation of

host responses.

Fig. 4. Prostaglandin E2 (PGE2) inhibits lipopolysaccha-

ride (LPS)-induced tumor necrosis factor-a (TNF-a) pro-duction by human monocytes. (A) Human peripheral

blood monocytes were stimulated with buffer, 1 lg/mlActinobacillus actinomycetemcomitans ( A.a.) LPS alone

or A.a LPS + indicated doses of PGE2 in the presence of

1 lM of indomethacin. After 48-h incubation, TNF-a levelsin the culture media were measured by enzyme-linked

immunosorbent assay. PGE2 inhibited LPS-induced TNF-aproduction in a dose-dependent manner; 11-deoxy-PGE1(a EP2/EP4 receptor agonist) and to a lesser extent but-

aprost (an EP2 receptor agonist), which are mediated by

cyclic AMP signaling, inhibited A.a. LPS-induced TNF-aproduction (data not shown). (B) Schema of PGE2 regu-

lation of LPS-induced TNF-a production in monocytes.

93


Matrix metalloproteinases are a family of zinc-

dependent endoproteases that degrade extracellular

matrix including collagen, gelatin, and proteoglycan

(9). A variety of matrix metalloproteinases, including

matrix metalloproteinase-1, -2, -3, -8, -9, and -13, are

associated with periodontal tissue destruction. Pros-

taglandin E2 induces the production of matrix met-

alloproteinases -2 and -13, which are involved in

prostaglandin E2-induced bone resorption, in mouse

calvaria possibly via EP4 receptors (80). In mouse

osteoblasts, prostaglandin E2 induces matrix metal-

loproteinse-1 gene expression by cyclic AMP-protein

kinase A-dependent pathways (59). In human

gingival fibroblasts and periodontal ligament cells,

prostaglandin E2 up- and down-regulates interleukin-

1-induced matrix metalloproteinase-3 production via

EP1 and EP2/EP4 receptors, respectively (118, 155). In

human periodontal ligament cells, prostaglandin E2down-regulates interleukin-1-induced matrix metal-

loproteinase-13 production via EP1 receptors and

tumor necrosis factor-a-induced matrix metallopro-teinase-13 production possibly via EP2/EP4 receptors

(92, 103). Matrix metalloproteinase-1 and matrix

metalloproteinase-9 production by monocytes/

macrophages in response to lipopolysaccharide,

denatured collagen, and osteonectin is regulated by

endogenous prostaglandin E2 (112, 124).

Therefore, it is likely that in certain settings, pros-

taglandin E2 not only functions as a proinflammatory

mediator but also possesses anti-inflammatory

properties in an autocrine or paracrine manner in

periodontal lesions. However, it remains unclear how

the dual effects of prostaglandin E2 are regulated.

Effect of prostaglandin E2 on bonemetabolism and periodontal tissueregeneration

The effect of prostaglandin E2 on bone metabolism is

complex and may be in some ways contradictory.

Generally, prostaglandin E2 is thought to be a potent

stimulator of bone resorption. In vitro, prostaglandin

E2 induces receptor activator of nuclear factor-jB inosteoblasts and stromal cells to form osteoclasts.

In vivo, it has been shown that 1 mg/ml prostaglan-

din E2 applied topically to the gingival sulcus induced

a marked increase in osteoclasts and that the appli-

cation of a combination of prostaglandin E2 and

lipopolysaccharide induced more osteoclasts than

prostaglandin E2 alone (78). Sakuma et al. (121) and

Miyaura et al. (80) reported impairment of osteoclast

formation in vitro by prostaglandin E2 in cultured

cells from EP4-deficient mice. Interleukin-1a, tumornecrosis factor-a, lipopolysaccharide, and basicfibroblast growth factor failed to induce osteoclast

formation in these cultures, suggesting that osteo-

clast formation is mediated via EP4 receptors by

prostaglandin E2, which was produced through

cyclooxygenase-2 (121). On the other hand, Li et al.

(67) reported that the osteoclastogenic response to

prostaglandin E2, parathyroid hormone, and 1,25

dihydroxyvitamin D in vitro was impaired in cultures

of cells from EP2-deficient mice. This discrepancy is

likely to reflect redundant roles of the two prosta-

glandin E receptor subtypes. Suzawa et al. (131)

showed that prostaglandin E2 induces bone resorp-

tion via EP4 and partially EP2 receptors in organ

culture. In an in vivo experiment, Sakuma et al. (120)

tested whether EP4 is crucial for bone resorption after

systemic lipolysaccharide injection. They demon-

strated that in EP4-deficient mice, expression of

receptor activator of nuclear factor-jB ligand andosteoclast formation were reduced, although in

wild-type mice they were increased. Recently, Suda

et al. (129) demonstrated that lipopolysaccharide

and interleukin-1 stimulated osteoclastogenesis by

enhancing receptor activator of nuclear factor-jBligand expression and depressing osteoprotegerin

production, which was mediated by cyclooxygenase-

2-dependent prostaglandin E2 production.

Periodontal ligament cells have similar character-

istics to osteoblasts, including their alkaline phos-

phatase activity. It has been shown that periodontal

ligament cells under mechanical stress induce

osteoclastogenesis by receptor activator of nuclear

factor-jB ligand up-regulation via prostaglandin E2synthesis (57). Nukaga et al. (104) showed that sti-

mulation of human periodontal ligament cells with

interleukin-1b induces receptor activator of nuclearfactor-jB ligand via EP2/EP4 receptors in a prosta-glandin E2-dependent manner. Tiranathanagul et al.

(136) showed that A. actinomycetmcomitans lipo-

polysaccharide induced receptor activator of nuclear

factor-jB ligand through the synthesis of prosta-glandins, possibly prostaglandin E2, in human

periodontal ligament cells. Sakata et al. (119) dem-

onstrated that interleukin-1b-induced osteoproteg-erin production in human periodontal ligament cells

was suppressed through endogenous prostaglandin

E2. These data suggest that periodontal ligament

cells stimulated with proinflammatory stimuli are

involved in bone metabolism in the periodontium by

regulating receptor activator of nuclear factor-jBligand and osteoprotegerin expression. Very recently,

94

Noguchi & Ishikawa

it has been demonstrated that prostaglandin E2enhances osteoprotegerin production in human gin-

gival fibroblasts (43).

Currently, studies with cell and organ cultures have

indicated that forms of prostaglandin E have a stim-

ulatory effect on not only bone resorption but also

bone formation. Clinical studies described new sub-

periosteal bone formation in infants with congenital

cardiac anomalies following long-term administra-

tion of prostaglandin E1 to maintain patency of the

ductus arteriosus (128, 139). Other studies in animals

and humans have demonstrated that systemic

and local administration of prostaglandin E1 and

prostaglandin E2 causes substantial bone formation

(40, 51, 54, 77).

Insulin-like growth factors are known to enhance

skeletal growth, and insulin-like growth factor-1

specifically promotes collagen synthesis by osteo-

blasts (75). It has been shown that prostaglandin E2promotes insulin growth factor-1 gene expression,

suggesting that this is at least one mechanism by

which prostaglandin E2 promotes bone formation (8).

Recently, Yoshida et al. (156) demonstrated, using

EP4-deficient mice and EP4 agonists, that prosta-

glandin E2 induces bone formation via EP4 receptors.

They suggest that prostaglandin E2 induces core

binding factor-a subunit 1 expression in osteoblasts.Furthermore, Zhang et al. (160) demonstrated that

cyclooxygenase-2 is required for both intramembra-

nous and endochondral bone formation during bone

repair and that the induction of core binding factor asubunit 1 andosterix is regulatedby cyclooxygenase-2,

possibly through prostaglandin E2.

The direct effect of osteoclasts on prostaglandin E2is inhibition of bone-resorbing activity via EP4receptors (71). Therefore, prostaglandin E2 plays an

important role for both bone resorption and bone

formation, and EP4 receptors may be responsible for

prostaglandin E2 regulation of bone metabolism.

Local application of prostaglandin E1 has been

shown to stimulate bone formation adjacent to the

site of delivery in the canine mandible (72). The use

of a stable prostaglandin E1 analog in a hamster

periodontitis model improved bone status (11). It has

also been reported that local delivery of prostaglan-

din E1 increases cementum, alveolar bone, and per-

iodontal ligament cell formation in adult dogs (73).

This treatment not only restored bone in the alveolar

process but also caused formation of new cementum

and periodontal ligament, resulting in regeneration of

the periodontium. Recently, it has been shown that in

mouse cementoblasts, prostaglandin E2 and prosta-

glandin F2a exert an anabolic effect on mineralization

through activation of protein kinase C signaling

possibly via EP1 and FP receptors, respectively (12).

However, Trombelli et al. (138) reported that mi-

soprostol, a prostaglandin E1 analog, has a limited

effect on bone and cementum regeneration in dogs

with supra-alveolar periodontal defects.

Given the diverse effects of prostaglandin E on

osteoclast and osteoblast activities reported in the

literature, the clinical effects of prostaglandin E on

bone metabolism and periodontal tissue regener-

ation remain unknown and merit further clinical

investigation.

Conclusions

It is clear that prostaglandins are involved in the

pathogenesis of periodontal diseases because a lot

of studies have indicated that in both animal

and human models traditional non-steroidal

anti-inflammatory drugs inhibit progression of the

diseases. According to recent researches, cyclo-

oxygenase-2 plays a crucial role in prostaglandin

production in periodontal disease and selective

cyclooxygenase-2 inhibitors are as efficacious as tra-

ditional non-steroidal anti-inflammatory drugs for

the inhibition of progression of periodontal disease in

animal models. Therefore, cyclooxygenase-2 inhibi-

tors may be effective for host modulatory therapy,

but careful clinical studies are necessary to prove it,

based on the understanding of the advantages and

disadvantages of cyclooxygenase-2 inhibitors. It has

been shown that cyclooxygenase-2 may be proin-

flammatory during the early phase of a carrageenan-

induced pleurisy, dominated by polymorphonuclear

leukocytes, but may aid resolution at the later,

mononuclear cell-dominated phase by generating an

alternative set of anti-inflammatory prostaglandins

including prostaglandin D2 and 15-deoxyD12,14 pros-

taglandin J2 (33). To better understand the roles of

prostaglandins in periodontal diseases, further stud-

ies about the effects of not only prostaglandin E2 but

also other prostaglandins including prostaglandin

F2a, prostaglandin I2, thromboxane A2, and prosta-

glandin D2 should be performed. As discussed above,

prostaglandin E2 has proinflammatory and anti-

inflammatory effects, depending on the receptors

used. Therefore, the precise roles of prostaglandins in

physiologic and pathologic conditions should be

determined by an intricate set of ligandreceptor

interactions that depend on multiple factors such as

ligand affinity, receptor expression profile, differen-

tial coupling to signal transduction pathways, and

95


cellular context in which the receptor is expressed.

The development of receptor-specific antagonists or

agonists may offer significant advantages and flexi-

bility over non-steroidal anti-inflammatory drugs

that non-selectively inhibit the synthesis of all pro-

staglandins.

References

1. Abramovitz M, Adam M, Boie Y, Carriere M, Denis D,

GodboutC, Lamontagne S, RochetteC, SawyerN, Tremblay

NM, Belley M, Gallant M, Dufresne C, Gareau Y, Ruel R,

JuteauH, LabelleM, Ouimet N,Metters KM. The utilization

of recombinant prostanoid receptors to determine the

affinities and selectivities of prostaglandins and related

analogs. Biochim Biophys Acta 2000: 1483: 285293.

2. Aoyagi T, Sugawara-Aoyagi M, Yamazaki K, Hara K.

Interleukin 4 (IL-4) and IL-6-producing memory T-cells in

peripheral blood and gingival tissue in periodontitis

patients with high serum antibody titers to Porphyro-

monas gingivalis. Oral Microbiol Immunol 1995: 10: 304

310.

3. Bastepe M, Ashby B. Identification of a region of the

C-terminal domain involved in short-term desensitization

of the prostaglandin EP4 receptor. Br J Pharmacol 1999:

126: 365371.

4. Bastien L, Sawyer N, Grygorczyk R, Metters KM, Adam M.

Cloning, functional expression, and characterization of

the human prostaglandin E2 receptor EP2 subtype. J Biol

Chem 1994: 269: 1187311877.

5. Bezerra MM, de Lima V, Alencar VB, Vieira IB, Brito GA,

Ribeiro RA, Rocha FA. Selective cyclooxygenase-2 inhibi-

tion prevents alveolar bone loss in experimental perio-

dontitis in rats. J Periodontol 2000: 71: 10091014.

6. Bhattacharya M, Peri KG, Almazan G, Ribeiro-da-Silva A,

Shichi H, Durocher Y, Abramovitz M, Hou X, Varma DR,

Chemtob S. Nuclear localization of prostaglandin E2 re-

ceptors. Proc Natl Acad Sci U S A 1998: 95: 1579215797.

7. Bhattacharya M, Peri K, Ribeiro-da-Silva A, Almazan G,

Shichi H, Hou X, Varma DR, Chemtob S. Localization of

functional prostaglandin E2 receptors EP3 and EP4 in the

nuclear envelope. J Biol Chem 1999: 274: 1571915724.

8. Bichell DP, Rotwein P, McCarthy TL. Prostaglandin E2rapidly stimulates insulin-like growth factor-I gene

expression in primary rat osteoblast cultures: evidence for

transcriptional control. Endocrinology 1993: 133: 1020

1028.

9. Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ,

Birkedal-Hansen B, DeCarlo A, Engler JA. Matrix metal-

loproteinases: a review. Crit Rev Oral Biol Med 1993: 4:

197250.

10. Buduneli N, Vardar S, Atilla G, Sorsa T, Luoto H, Baylas H.

Gingival crevicular fluid matrix metalloproteinase-8 levels

following adjunctive use of meloxicam and initial phase of

periodontal therapy. J Periodontol 2002: 73: 103109.

11. Caillon P, Saffar JL. Improvement of gingival and alveolar

bone status in periodontitis-affected hamsters treated

with 15-methyl prostaglandin E1. J Periodontal Res 1994:

29: 138145.

12. Camargo PM, Lagos R, Pirih FQ, Benitez A, Nervina JM,

Tetradis S. Prostaglandins E2 and F2a enhance differenti-

ation of cementoblastic cells. J Periodontol 2005: 76: 303

309.

13. Cavanaugh PF Jr, Mcdonald JS, Pavelic L, Limardi RJ,

Gluckman JL, Pavelic ZP. Immunohistochemical localiza-

tion of prostaglandin H synthase isoenzyme proteins in

the gingival tissue of patients with periodontitis. Inflam-

mopharmacology 1995: 3: 109119.

14. Chandrasekharan NV, Dai H, Roos KL, Evanson NK,

Tomsik J, Elton TS, Simmons DL. COX-3, a cyclooxy-

genase-1 variant inhibited by acetaminophen and other

analgesic/antipyretic drugs: cloning, structure, and

expression. Proc Natl Acad Sci U S A 2002: 99: 13926

13931.

15. Chang YC, Tsai CH, Yang SH, Liu CM, Chou MY. Induction

of cyclooxygenase-2 mRNA and protein expression in

human gingival fibroblasts stimulated with nicotine.

J Periodontal Res 2003: 38: 496501.

16. Chomarat P, Banchereau J. An update on interleukin-4

and its receptor. Eur Cytokine Network 1997: 8: 333344.

17. Choudhry MA, Hockberger PE, Sayeed MM. PGE2 sup-

presses mitogen-induced Ca2+ mobilization in T cells.

Am J Physiol 1999: 277: R17411748.

18. Choudhry MA, Ahmed Z, Sayeed MM. PGE2-mediated

inhibition of T cell p59(fyn) is independent of cAMP.

Am J Physiol 1999: 277: C302C309.

19. Coleman RA, Smith WL, Narumiya S. International Union

of Pharmacology classification of prostanoid receptors:

properties, distribution, and structure of the receptors and

their subtypes. Pharmacol Rev 1994: 46: 205229.

20. Czuszak CA, Sutherland DE, Billman MA, Stein SH. Pros-

taglandin E2 potentiates interleukin-1b-induced interleu-kin-6 production by human gingival fibroblasts. J Clin

Periodontol 1996: 23: 635640.

21. Desai S, April H, Nwaneshiudu C, Ashby B. Comparison of

agonist-induced internalization of the human EP2 and EP4prostaglandin receptors: role of the carboxyl terminus in

EP4 receptor sequestration. Mol Pharmacol 2000: 58:

12791286.

22. Diamond MS, Staunton DE, Marlin SD, Springer TA.

Binding of the integrin Mac-1 (CD11b/CD18) to the third

immunoglobulin-like domain of ICAM-1 (CD54) and its

regulation by glycosylation. Cell 1991: 65: 961971.

23. Ebersole JL, Taubman MA. The protective nature of host

responses in periodontal diseases. Periodontol 2000 1994:

5: 112141.

24. ElAttar TM. Prostaglandin E2 in human gingiva in health

and disease and its stimulation by female sex steroids.

Prostaglandins 1976: 11: 331341.

25. Endo T, Ogushi F, Sone S. LPS-dependent cyclooxygenase-

2 induction in human monocytes is down-regulated by

IL-13, but not IFN-c. J Immunol 1996: 156: 22402246.26. Fedyk ER, Harris SG, Padilla J, Phipps RP. Prostaglandin

receptors of the EP2 and EP4 subtypes regulate B lym-

phocyte activation and differentiation to IgE-secreting

cells. Adv Exp Med Biol 1997: 433: 153157.

27. FitzGerald GA. COX-2 and beyond: approaches to pros-

taglandin inhibition in human disease. Nat Rev Drug

Discov 2003: 2: 879890.

28. FitzGerald GA, Patrono C. The coxibs, selective inhibitors

of cyclooxygenase-2. N Engl J Med 2001: 345: 433442.

96

Noguchi & Ishikawa

29. Fokkema SJ, Loos BG, Slegte C, van der Velden U. A type 2

response in lipopolysaccharide (LPS)-stimulated whole

blood cell cultures from periodontitis patients. Clin Exp

Immunol 2002: 127: 374378.

30. Fujihashi K, Yamamoto M, Hiroi T, Bamberg TV, McGhee

JR, Kiyono H. Selected Th1 and Th2 cytokine mRNA

expression by CD4+ T cells isolated from inflamed human

gingival tissues. Clin Exp Immunol 1996: 103: 422428.

31. Funk CD, Furci L, FitzGerald GA, Grygorczyk R, Rochette

C, Bayne MA, Abramovitz M, Adam M, Metters KM. Clo-

ning and expression of a cDNA for the human prosta-

glandin E receptor EP1 subtype. J Biol Chem 1993: 268:

2676726772.

32. Gemmell E, Yamazaki K, Seymour GJ. Destructive perio-

dontitis lesions are determined by the nature of the

lymphocytic response. Crit Rev Oral Biol Med 2002: 13:

1734.

33. Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-

Clark MJ, Willoughby DA. Inducible cyclooxygenase may

have anti-inflammatory properties. Nat Med 1999: 5: 698

701.

34. Goodson JM, Dewhirst FE, Brunetti A. Prostaglandin E2levels and human periodontal disease. Prostaglandins

1974: 6: 8185.

35. Gopikrishna V, Parameswaran A. Effectiveness of pro-

phylactic use of rofecoxib in comparison with ibuprofen

on postendodontic pain. J Endod 2003: 29: 6264.

36. Gurgel BC, Duarte PM, Nociti FH Jr, Sallum EA, Casati MZ,

Sallum AW, de Toledo S. Impact of an anti-inflammatory

therapy and its withdrawal on the progression of experi-

mental periodontitis in rats. J Periodontol 2004: 75: 1613

1618.

37. Harrell JC, Stein SH. Prostaglandin E2 regulates gingival

mononuclear cell immunoglobulin production. J Period-

ontol 1995: 66: 222227.

38. Hart PH, Vitti GF, Burgess DR, Whitty GA, Piccoli DS,

Hamilton JA. Potential antiinflammatory effects of inter-

leukin 4: suppression of human monocyte tumor necrosis

factor a, interleukin 1, and prostaglandin E2. Proc NatlAcad Sci U S A 1989: 86: 38033807.

39. Hayashi Y, Kobayashi M, Kuwata H, Atsumi G, Deguchi K,

Feng Wei X, Kudo I, Hasegawa K. Interferon-c and inter-leukin 4 inhibit interleukin 1b-induced delayed prosta-glandin E2 generation through suppression of

cyclooxygenase-2 expression in human fibroblasts. Cyto-

kine 2000: 12: 603612.

40. High WB. Effects of orally administered prostaglandin E2on cortical bone turnover in adult dogs: a histomorpho-

metric study. Bone 1987: 8: 363373.

41. Hla T, Neilson K. Human cyclooxygenase-2 cDNA. Proc

Natl Acad Sci U S A 1992: 89: 73847388.

42. Holzhausen M, Rossa C Jr, Marcantonio E Jr, Nassar PO,

Spolidorio DM, Spolidorio LC. Effect of selective

cyclooxygenase-2 inhibition on the development of liga-

ture-induced periodontitis in rats. J Periodontol 2002: 73:

10301036.

43. Hormdee D, Nagasawa T, Kiji M, Yashiro R, Kobayashi H,

Koshy G, Noguchi K, Nitta H, Ishikawa I. Protein kinase A-

dependent osteoprotegerin production on interleukin-1

stimulation in human gingival fibroblasts is distinct from

periodontal ligament fibroblasts. Clin Exp Immunol 2005:

142: 490497.

44. Howell TH, Jeffcoat MK, Goldhaber P, Reddy MS, Kaplan

ML, Johnson HG, Hall CM, Williams RC. Inhibition of

alveolar bone loss in beagles with the NSAID naproxen.


45. Howell TH, Fiorellini J, Weber HP, Williams RC. Effect of

the NSAID piroxicam, topically administered, on the

development of gingivitis in beagle dogs. J Periodontal Res

1991: 26: 180183.

46. Irie A, Sugimoto Y, Namba T, Harazono A, Honda A,

Watabe A, Negishi M, Narumiya S, Ichikawa A. Third

isoform of the prostaglandin-E-receptor EP2 subtype with

different C-terminal tail coupling to both stimulation and

inhibition of adenylate cyclase. Eur J Biochem 1993: 217:

313318.

47. Ishihara Y, Zhang JB, Quinn SM, Schenkein HA, Best AM,

Barbour SE, Tew JG. Regulation of immunoglobulin G2

production by prostaglandin E2 and platelet-activating

factor. Infect Immun 2000: 68: 15631568.

48. Iwasaki K, Noguchi K, Ishikawa I. Prostaglandin E2 and I2regulate intercellular adhesion molecule-1 expression in

interleukin-1b-stimulated human gingival fibroblasts.J Periodontal Res 1999: 34: 97104. Erratum in: J Perio-

dontal Res 1999: 34: 97232.

49. Iwasaki K, Noguchi K, Endo H, Kondo H, Ishikawa I.

Prostaglandin E2 downregulates interleukin-12 production

through EP4 receptors in human monocytes stimulated

with lipopolysaccharide from Actinobacillus actinomyce-

temcomitans and interferon-gamma. Oral Microbiol

Immunol 2003: 18: 150155.

50. Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler

JD. The codependence of angiogenesis and chronic

inflammation. FASEB J 1997: 11: 457465.

51. Jee WS, Mori S, Li XJ, Chan S. Prostaglandin E2 enhances

cortical bone mass and activates intracortical bone

remodeling in intact and ovariectomized female rats. Bone

1990: 11: 253266.

52. Jeffcoat MK, Page R, Reddy M, Wannawisute A, Waite P,

Palcanis K, Cogen R, Williams RC, Basch C. Use of digital

radiography to demonstrate the potential of naproxen as

an adjunct in the treatment of rapidly progressive perio-

dontitis. J Periodontal Res 1991: 26: 415421.

53. Jones DA, Carlton DP, McIntyre TM, Zimmerman GA,

Prescott SM. Molecular cloning of human prostaglandin

endoperoxide synthase type II and demonstration of

expression in response to cytokines. J Biol Chem 1993:

268: 90499054.

54. Jorgensen HR, Svanholm H, Host A. Bone formation

induced in an infant by systemic prostaglandin-E2administration. Acta Orthop Scand 1988: 59: 464466.

55. Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA,

Egger M. Risk of cardiovascular events and rofecoxib:

cumulative meta-analysis. Lancet 2004: 364: 20212029.

56. Kabashima K, Sakata D, Nagamachi M, Miyachi Y, Inaba

K, Narumiya S. Prostaglandin E2-EP4 signaling initiates

skin immune responses by promoting migration and

maturation of Langerhans cells. Nat Med 2003: 9: 744

749.

57. Kanzaki H, Chiba M, Shimizu Y, Mitani H. Periodontal

ligament cells under mechanical stress induce osteo-

clastogenesis by receptor activator of nuclear factor jBligand up-regulation via prostaglandin E2 synthesis. J Bone

Miner Res 2002: 17: 210220.

97


58. Katamura K, Shintaku N, Yamauchi Y, Fukui T, Ohshima Y,

Mayumi M, Furusho K. Prostaglandin E2 at priming of

naive CD4+ T cells inhibits acquisition of ability to pro-

duce IFN-c and IL-2, but not IL-4 and IL-5. J Immunol1995: 155: 46044612.

59. Kim CH, Park YG, Noh SH, Kim YK. PGE2 induces the gene

expression of bone matrix metalloproteinase-1 in mouse

osteoblasts by cAMP-PKA signaling pathway. Int J Bio-

chem Cell Biol 2005: 37: 375385.

60. Kornman KS, Blodgett RF, Brunsvold M, Holt SC. Effects of

topical applications of meclofenamic acid and ibuprofen

on bone loss, subgingival microbiota and gingival PMN

response in the primate Macaca fascicularis. J Periodontal

Res 1990: 25: 300307.

61. Kotani M, Tanaka I, Ogawa Y, Usui T, Tamura N, Mori K,

Narumiya S, Yoshimi T, Nakao K. Structural organization

of the human prostaglandin EP3 receptor subtype gene

(PTGER3). Genomics 1997: 40: 425434.

62. Kraemer SA, Meade EA, DeWitt DL. Prostaglandin endo-

peroxide synthase gene structure: identification of the

transcriptional start site and 5-flanking regulatorysequences. Arch Biochem Biophys 1992: 293: 391400.

63. Kujubu DA, Fletcher BS, Varnum BC, Lim RL, Hershman

HR. TIS10, a phorbol ester tumor promoter-inducible

mRNA from Swiss 3T3 cells, encodes a novel prostaglan-

din synthase/cyclooxygenase homologue. J Biol Chem

1991: 266: 1286612872.

64. Kunii R, Nemoto E, Kanaya S, Tsubahara T, Shimauchi H.

Expression of CD13/aminopeptidase N on human gingival

fibroblasts and up-regulation upon stimulation with

interleukin-4 and interleukin-13. J Periodontal Res 2005:

40: 138146.

65. Lee SH, Soyoola E, Chanmugam P, Hart S, Sun W, Zhong

H, Liou S, Simmons D, Hwang D. Selective expression of

mitogen-inducible cyclooxygenase in macrophages sti-

mulated with lipopolysaccharide. J Biol Chem 1992: 267:

2593425938.

66. Li KL, Vogel R, Jeffcoat MK, Alfano MC, Smith MA, Collins

JG, Offenbacher S. The effect of ketoprofen creams on

periodontal disease in rhesus monkeys. J Periodontal Res

1996: 31: 525532.

67. Li X, Okada Y, Pilbeam CC, Lorenzo JA, Kennedy CR,

Breyer RM, Raisz LG. Knockout of the murine prosta-

glandin EP2 receptor impairs osteoclastogenesis in vitro.

Endocrinology 2000: 141: 20542061.

68. Li Y, Xu L, Hasturk H, Kantarci A, Depalma SR, Van Dyke

TE. Localized aggressive periodontitis is linked to human

chromosome 1q25. Hum Gen 2004: 114: 291297.

69. Lohinai Z, Stachlewitz R, Szekely AD, Feher E, Dezsi L,

Szabo C. Evidence for the expression of cyclooxygenase-2

enzyme in periodontitis. Life Sci 2001: 70: 279290.

70. Malmstrom K, Daniels S, Kotey P, Seidenberg BC, Des-

jardins PJ. Comparison of rofecoxib and celecoxib, two

cyclooxygenase-2 inhibitors, in postoperative dental pain:

a randomized, placebo- and active-comparator-controlled

clinical trial. Clin Ther 1999: 21: 16531663.

71. Mano M, Arakawa T, Mano H, Nakagawa M, Kaneda T,

Kaneko H, Yamada T, Miyata K, Kiyomura H, Kumegawa

M, Hakeda Y. Prostaglandin E2 directly inhibits bone-

resorbing activity of isolated mature osteoclasts mainly

through the EP4 receptor. Calcif Tissue Int 2000: 67:

8592.

72. Marks SC Jr, Miller SC. Local infusion of prostaglandin E1stimulates mandibular bone formation in vivo. J Oral

Pathol 1988: 17: 500505.

73. Marks SC Jr, Miller SC. Local delivery of prostaglandin E1induces periodontal regeneration in adult dogs. J Perio-

dontal Res 1994: 29: 103108.

74. Masferrer JL, Reddy ST, Zweifel BS, Seibert K, Needleman

P, Gilbert RS, Herschman HR. In vivo glucocorticoids

regulate cyclooxygenase-2 but not cyclooxygenase-1 in

peritoneal macrophages. J Pharmacol Exp Ther 1994: 270:

13401344.

75. McCarthy TL, Centrella M. Local IGF-I expression and

bone formation. Growth Horm IGF Res 2001: 11: 213219.

76. Meja KK, Barnes PJ, Giembycz MA. Characterization of

the prostanoid receptor(s) on human blood monocytes

at which prostaglandin E2 inhibits lipopolysaccharide-

induced tumour necrosis factor-a generation. Br J Phar-macol 1997: 122: 149157.

77. Miller SC, Marks SC Jr. Local stimulation of new bone

formation by prostaglandin E1: quantitative histomorph-

ometry and comparison of delivery by minipumps and

controlled-release pellets. Bone 1993: 14: 143151.

78. Miyauchi M, Ijuhin N, Nikai H, Takata T, Ito H, Ogawa I.

Effect of exogenously applied prostaglandin E2 on alveolar

bone loss-histometric analysis. J Periodontol 1992: 63:

405411.

79. Miyauchi M, Hiraoka M, Oka H, Sato S, Kudo Y, Ogawa I,

Noguchi K, Ishikawa I, Takata T. Immuno-localization of

COX-1 and COX-2 in the rat molar periodontal tissue after

topical application of lipopolysaccharide. Arch Oral Biol

2004: 49: 739746.

80. Miyaura C, Inada M, Suzawa T, Sugimoto Y, Ushikubi F,

Ichikawa A, Narumiya S, Suda T. Impaired bone resorp-

tion to prostaglandin E2 in prostaglandin E receptor EP4-

knockout mice. J Biol Chem 2000: 275: 1981919823.

81. Moraitis D, Du B, De Lorenzo MS, Boyle JO, Weksler BB,

Cohen EG, Carew JF, Altorki NK, Kopelovich L, Subbara-

maiah K, Dannenberg AJ. Levels of cyclooxygenase-2 are

increased in the oral mucosa of smokers: evidence for the

role of epidermal growth factor receptor and its ligands.

Cancer Res 2005: 65: 664670.

82. Morita I. Distinct functions of COX-1 and COX-2. Prosta-

glandins Other Lipid Mediat 2002: 6869: 165175.

83. Morrison BW, Christensen S, Yuan W, Brown J, Arnlani S,

Seidenberg B. Analgesic efficacy of the cyclooxygenase-2-

specific inhibitor rofecoxib in post-dental surgery pain:

randomized, controlled trial. Clin Ther 1999: 21: 943953.

84. Morton RS, Dongari-Bagtzoglou AI. Cyclooxygenase-2 is

upregulated in inflamed gingival tissues. J Periodontol

2001: 72: 461469.

85. Murakami S, Shimabukuro Y, Saho T, Hino E, Kasai D,

Hashikawa T, Hirano H, Okada H. Immunoregulatory

roles of adhesive interactions between lymphocytes and

gingival fibroblasts. J Periodontal Res 1997: 32: 110114.

86. Namba T, Sugimoto Y, Negishi M, Irie A, Ushikubi F,

Kakizuka A, Ito S, Ichikawa A, Narumiya S. Alternative

splicing of C-terminal tail of prostaglandin E receptor

subtype EP3 determines G-protein specificity. Nature

1993: 365: 166170.

87. Narumiya S, Sugimoto Y, Ichikawa A. Prostanoid recep-

tors: structures, properties, and functions. Physiol Rev

1999: 79: 11931226.

98

Noguchi & Ishikawa

88. Nataraj C, Thomas DW, Tilley SL, Nguyen MT, Mannon R,

Koller BH, Coffman TM. Receptors for prostaglandin E2that regulate cellular immune responses in the mouse.

J Clin Invest 2001: 108: 12291235.

89. Niiro H, Otsuka T, Tanabe T, Hara S, Kuga S, Nemoto Y,

Tanaka Y, Nakashima H, Kitajima S, Abe M, Niho Y.

Inhibition by interleukin-10 of inducible cyclooxygenase

expression in lipopolysaccharide-stimulated monocytes:

its underlying mechanism in comparison with interleukin-

4. Blood 1995: 85: 37363745.

90. Niiro H, Otsuka T, Izuhara K, Yamaoka K, Ohshima K,

Tanabe T, Hara S, Nemoto Y, Tanaka Y, Nakashima H,

Niho Y. Regulation by interleukin-10 and interleukin-4 of

cyclooxygenase-2 expression in human neutrophils. Blood

1997: 89: 16211628.

91. Nishigaki N, Negishi M, Honda A, Sugimoto Y, Namba T,

Narumiya S, Ichikawa A. Identification of prostaglandin E

receptor EP2 cloned from mastocytoma cells EP4 sub-type. FEBS Lett 1995: 364: 339341.

92. Nishikawa M, Yamaguchi Y, Yoshitake K, Saeki Y. Effects of

TNFa and prostaglandin E2 on the expression of MMPs inhuman periodontal ligament fibroblasts. J Periodontal Res

2002: 37: 167176.

93. Noguchi K, Yanai M, Shitashige M, Nishihara T, Morita I,

Murota S, Ishikawa I. Prostaglandin production via

induction of cyclooxygenase-2 by human gingival fibro-

blasts stimulated with lipopolysaccharides. Inflammation

1996: 20: 555568.

94. Noguchi K, Iwasaki K, Shitashige M, Ishikawa I. Prosta-

glandin E2 receptors of the EP2 and EP4 subtypes down-

regulate tumor necrosis factor a-induced intercellularadhesion molecule-1 expression in human gingival fibro-

blasts. J Periodontal Res 1999: 34: 478485.

95. Noguchi K, Shitashige M, Murota S, Ishikawa I. Interleu-

kin-4 and interferon-c inhibit prostaglandin production byinterleukin-1b-stimulated human periodontal ligamentfibroblasts. Inflammation 1999: 23: 113.

96. Noguchi K, Shitashige M, Ishikawa I. Involvement of

cyclooxygenase-2 in interleukin-1a-induced prostaglandinproduction by human periodontal ligament cells. J Peri-

odontol 1999: 70: 902908.

97. Noguchi K, Yanai M, Shitashige M, Nishihara T, Ishikawa I.

Cyclooxygenase-2-dependent prostaglandin production

by peripheral blood monocytes stimulated with lipopoly-

saccharides isolated from periodontopathogenic bacteria.

J Periodontol 2000: 71: 15681575.

98. Noguchi K, Iwasaki K, Shitashige M, Endo H, Kondo H,

Ishikawa I. Cyclooxygenase-2-dependent prostaglandin

E2 down-regulates intercellular adhesion molecule-1

expression via EP2/EP4 receptors in interleukin-1b-sti-mulated human gingival fibroblasts. J Dent Res 2000: 79:

19551961.

99. Noguchi K, Shitashige M, Endo H, Kondo H, Yotsumoto Y,

Izumi Y, Nitta H, Ishikawa I. Involvement of cyclooxyge-

nase-2 in serum-induced prostaglandin production by

human oral gingival epithelial cells. J Periodontal Res 2001:

36: 124130.

100. Noguchi K, Iwasaki K, Shitashige M, Umeda M, Izumi Y,

Murota S, Ishikawa I. Downregulation of lipopolysaccha-

ride-induced intercellular adhesion molecule-1 expression

via EP2/EP4 receptors by prostaglandin E2 in human

fibroblasts. Inflammation 2001: 25: 7581.

101. Noguchi K, Shitashige M, Endo H, Kondo H, Ishikawa I.

Binary regulation of interleukin(IL)-6 production by EP1and EP2/EP4 subtypes of PGE2 receptors in IL-1b-stimu-lated human gingival fibroblasts. J Periodontal Res 2002:

37: 2936.

102. Noguchi T, Shiba H, Komatsuzawa H, Mizuno N, Uchida

Y, Ouhara K, Asakawa R, Kudo S, Kawaguchi H, Sugai M,

Kurihara H. Syntheses of prostaglandin E2 and E-cadh-

erin and gene expression of beta-defensin-2 by human

gingival epithelial cells in response to Actinobacillus

actinomycetemcomitans. Inflammation 2003: 27: 341

349.

103. Noguchi K, Ruwanpura SM, Yan M, Yoshida N, Ishikawa I.

Down-regulation of interleukin-1alpha-induced matrix

metalloproteinase-13 expression via EP1 receptors by

prostaglandin E2 in human periodontal ligament cells.

Oral Microbiol Immunol 2005: 20: 5659.

104. Nukaga J, Kobayashi M, Shinki T, Song H, Takada T,

Takiguchi T, Kamijo R, Hasegawa K. Regulatory effects of

interleukin-1b and prostaglandin E2 on expression ofreceptor activator of nuclear factor-jB ligand in humanperiodontal ligament cells. J Periodontol 2004: 75: 249

259.

105. Nyman S, Schroeder HE, Lindhe J. Suppression of

inflammation and bone resorption by indomethacin dur-

ing experimental periodontitis in dogs. J Periodontol 1979:

50: 450461.

106. ONeill GP, Ford-Hutchinson AW. Expression of mRNA for

cyclooxygenase-1 and cyclooxygenase-2 in human tissues.

FEBS Lett 1993: 330: 156160.

107. Offenbacher S, Odle BM, Gray RC, Van Dyke TE. Crevic-

ular fluid prostaglandin E levels as a measure of the per-

iodontal disease status of adult and juvenile periodontitis

patients. J Periodontal Res 1984: 19: 113.

108. Offenbacher S, Odle BM, Van Dyke TE. The use of

crevicular fluid prostaglandin E2 levels as a predictor of

periodontal attachment loss. J Periodontal Res 1986: 21:

101112.

109. Offenbacher S, Williams RC, Jeffcoat MK, Howell TH, Odle

BM, Smith MA, Hall CM, Johnson HG, Goldhaber P.

Effects of NSAIDs on beagle crevicular cyclooxygenase

metabolites and periodontal bone loss. J Periodontal Res

1992: 27: 207213.

110. Ohm K, Albers HK, Lisboa BP. Measurement of eight

prostaglandins in human gingival and periodontal disease

using high pressure liquid chromatography and radioim-

munoassay. J Periodontal Res 1984: 19: 501511.

111. Paquette DW, Williams RC. Modulation of host inflam-

matory mediators as a treatment strategy for periodontal

diseases. Periodontol 2000 2000: 24: 239252.

112. Pentland AP, Shapiro SD, Welgus HG. Agonist-induced

expression of tissue inhibitor of metalloproteinases and

metalloproteinases by human macrophages is regulated

by endogenous prostaglandin E2 synthesis. J Invest Der-

matol 1995: 104: 5257.

113. Pourzarandian A, Watanabe H, Ruwanpura SM, Aoki A,

Noguchi K, Ishikawa I. Er:YAG laser irradiation increases

prostaglandin E production via the induction of cyclo-

oxygenase-2 mRNA in human gingival fibroblasts.


114. Reddy MS, Palcanis KG, Barnett ML, Haigh S, Charles CH,

Jeffcoat MK. Efficacy of meclofenamate sodium (Meclo-

99


men) in the treatment of rapidly progressive periodontitis.

J Clin Periodontol 1993: 20: 635640.

115. Regan JW, Bailey TJ, Pepperl DJ, Pierce KL, Bogardus AM,

Donello JE, Fairbairn CE, Kedzie KM, Woodward DF, Gil

DW. Cloning of a novel human prostaglandin receptor

with characteristics of the pharmacologically defined EP2subtype. Mol Pharmacol 1994: 46: 213220.

116. Roberts FA, Houston LS, Lukehart SA, Mancl LA, Persson

GR, Page RC. Periodontitis vaccine decreases local pros-

taglandin E2 levels in a primate model. Infect Immun 2004:

72: 11661168.

117. Ruggeri P, Nicocia G, Venza I, Venza M, Valenti A, Teti D.

Polyamine metabolism in prostaglandin E2-treated

human T lymphocytes. Immunopharmacol Immunotoxi-

col 2000: 22: 117129.

118. Ruwanpura SM, Noguchi K, Ishikawa I. Prostaglandin E2regulates interleukin-1beta-induced matrix metalloprote-

inase-3 production in human gingival fibroblasts. J Dent

Res 2004: 83: 260265.

119. Sakata M, Shiba H, Komatsuzawa H, Fujita T, Uchida Y,

Yoshino H, Ogawa T, Kawaguchi H, Kurihara H. Osteo-

protegerin levels increased by interleukin-1beta in human

periodontal ligament cells are suppressed through pros-

taglandin E2 synthesized de novo. Cytokine 2002: 18: 133

139.

120. Sakuma Y, Tanaka K, Suda M, Komatsu Y, Yasoda A, Miura

M, Ozasa A, Narumiya S, Sugimoto Y, Ichikawa A, Ush-

ikubi F, Nakao K. Impaired bone resorption by lipopoly-

saccharide in vivo in mice deficient in the prostaglandin E

receptor EP4 subtype. Infect Immun 2000: 68: 68196825.

121. Sakuma Y, Tanaka K, Suda M, Yasoda A, Natsui K, Tanaka

I, Ushikubi F, Narumiya S, Segi E, Sugimoto Y, Ichikawa A,

Nakao K. Crucial involvement of the EP4 subtype of

prostaglandin E receptor in osteoclast formation by pro-

inflammatory cytokines and lipopolysaccharide. J Bone

Miner Res 2000: 15: 218227.

122. Sakurai Y, Yamaguchi M, Abiko Y. Inhibitory effect of low-

level laser irradiation on LPS-stimulated prostaglandin E2production and cyclooxygenase-2 in human gingival

fibroblasts. Eur J Oral Sci 2000: 108: 2934.

123. Sfakianakis A, Barr CE, Kreutzer DL. Actinobacillus actin-

omycetemcomitans-induced expression of IL-1a and IL-1bin human gingival epithelial cells: role in IL-8 expression.

Eur J Oral Sci 2001: 109: 393401.

124. Shankavaram UT, DeWitt DL, Funk SE, Sage EH, Wahl LM.

Regulation of human monocyte matrix metalloproteinases

by SPARC. J Cell Physiol 1997: 173: 327334.

125. Shapira L, Soskolne WA, Van Dyke TE. Prostaglandin E2secretion, cell maturation, and CD14 expression by

monocyte-derived macrophages from localized juvenile

periodontitis patients. J Periodontol 1996: 67: 224228.

126. Shimizu N, Ozawa Y, Yamaguchi M, Goseki T, Ohzeki K,

Abiko Y. Induction of COX-2 expression by mechanical

tension force in human periodontal ligament cells.

J Periodontol 1998: 69: 670677.

127. Shinomiya S, Naraba H, Ueno A, Utsunomiya I, Maruyama

T, Ohuchida S, Ushikubi F, Yuki K, Narumiya S, Sugimoto

Y, Ichikawa A, Oh-ishi S. Regulation of TNFa and inter-leukin-10 production by prostaglandins I2 and E2: studies

with prostaglandin receptor-deficient mice and prosta-

glandin E-receptor subtype-selective synthetic agonists.

Biochem Pharmacol 2001: 61: 11531160.

128. Sone K, Tashiro M, Fujinaga T, Tomomasa T, Tokuyama K,

Kuroume T. Long-term low-dose prostaglandin E1administration. J Pediatr 1980: 97: 866867.

129. Suda K, Udagawa N, Sato N, Takami M, Itoh K, Woo JT,

Takahashi N, Nagai K. Suppression of osteoprotegerin

expression by prostaglandin E2 is crucially involved

in lipopolysaccharide-induced osteoclast formation.

J Immunol 2004: 172: 25042510.

130. Sugimoto Y, Namba T, Honda A, Hayashi Y, Negishi M,

Ichikawa A, Narumiya S. Cloning and expression of a

cDNA for mouse prostaglandin E receptor EP3 subtype.

J Biol Chem 1992: 267: 64636466.

131. Suzawa T, Miyaura C, Inada M, Maruyama T, Sugimoto Y,

Ushikubi F, Ichikawa A, Narumiya S, Suda T. The role of

prostaglandin E receptor subtypes (EP1, EP2, EP3, and

EP4) in bone resorption: an analysis using specific agon-

ists for the respective EPs. Endocrinology 2000: 141: 1554

1559.

132. Takayama K, Garcia-Cardena G, Sukhova GK, Comander

J, Gimbrone MA Jr, Libby P. Prostaglandin E2 suppresses

chemokine production in human macrophages

through the EP4 receptor. J Biol Chem 2002: 277: 44147

44154.

133. Takigawa M, Takashiba S, Takahashi K, Arai H, Kurihara

H, Murayama Y. Prostaglandin E2 inhibits interleukin-6

release but not its transcription in human gingival fibro-

blasts stimulated with interleukin-1b or tumor necrosisfactor-a. J Periodontol 1994: 65: 11221127.

134. Tanabe T, Tohnai N. Cyclooxygenase isozymes and their

gene structures and expression. Prostaglandins Other

Lipid Mediat 2002: 6869: 95114.

135. Tanaka S, Barbour SE, Best AM, Schenkein HA, Tew JG.

Prostaglandin E2-mediated regulation of immunoglobulin

G2 via interferon c. J Periodontol 2003: 74: 771779.136. Tiranathanagul S, Yongchaitrakul T, Pattamapun K,

Pavasant P. Actinobacillus actinomycetemcomitans lipo-

polysaccharide activates matrix metalloproteinase-2

and increases receptor activator of nuclear factor-jBligand expression in human periodontal ligament cells.

J Periodontol 2004: 75: 16471654.

137. Tokoro Y, Matsuki Y, Yamamoto T, Suzuki T, Hara K.

Relevance of local Th-2 type cytokine mRNA expression in

immunocompetent infiltrates in inflamed gingival tissue

to periodontal diseases. Clin Exp Immunol 1997: 107: 166

174.

138. Trombelli L, Lee MB, Promsudthi A, Guglielmoni PG,

Wikesjo UM. Periodontal repair in dogs: histologic obser-

vations of guided tissue regeneration with a prostaglandin

E1 analog/methacrylate composite. J Clin Periodontol

1999: 26: 381387.

139. Ueda K, Saito A, Nakano H, Aoshima M, Yokota M,

Muraoka R, Iwaya T. Cortical hyperostosis following long-

term administration of prostaglandin E1 in infants with

cyanotic congenital heart disease. J Pediatr 1980: 97: 834

836.

140. Vane JR. Inhibition of prostaglandin synthesis as a

mechanism of action for aspirin-like drugs. Nat New Biol

1971: 231: 232235.

141. Vane J. Towards a better aspirin. Nature 1994: 367: 215

216.

142. Vardar S, Baylas H, Huseyinov A. Effects of selective

cyclooxygenase-2 inhibition on gingival tissue levels of

100

Noguchi & Ishikawa

prostaglandin E2 and prostaglandin F2a and clinical

parameters of chronic periodontitis. J Periodontol 2003:

74: 5763.

143. Waite IM, Saxton CA, Young A, Wagg BJ, Corbett M. The

periodontal status of subjects receiving non-steroidal

anti-inflammatory drugs. J Periodontal Res 1981: 16: 100

108.

144. Wallace JL, McKnight W, Reuter BK, Vergnolle N. NSAID-

induced gastric damage in rats: requirement for inhibition

of both cyclooxygenase 1 and 2. Gastroenterology 2000:

119: 706714.

145. Watanabe K, Tanaka Y, Morimoto Y, Yahata K, Zeki K,

Fujihara T, Yamashita U, Eto S. Interleukin-4 as a potent

inhibitor of bone resorption. Biochem Biophys Res Com-

mun 1990: 172: 10351041.

146. Williams RC, Jeffcoat MK, Kaplan ML, Goldhaber P,

Johnson HG, Wechter WJ. Flurbiprofen: a potent inhibitor

of alveolar bone resorption in beagles. Science 1985: 227:

640642.

147. Williams RC, Jeffcoat MK, Howell TH, Hall CM, Johnson

HG, Wechter WJ, Goldhaber P. Indomethacin or flurbi-

profen treatment of periodontitis in beagles: comparison

of effect on bone loss. J Periodontal Res 1987: 22: 403

407.

148. Williams RC, Offenbacher S, Jeffcoat MK, Howell TH,

Johnson HG, Hall CM, Wechter WJ, Goldhaber P. Indo-

methacin or flurbiprofen treatment of periodontitis in

beagles: effect on crevicular fluid arachidonic acid

metabolites compared with effect on alveolar bone loss.


149. Williams RC, Jeffcoat MK, Howell TH, Reddy MS, Johnson

HG, Hall CM, Goldhaber P. Topical flurbiprofen treatment

of periodontitis in beagles. J Periodontal Res 1988: 23: 166

169.

150. Williams RC, Jeffcoat MK, Howell TH, Reddy MS, Johnson

HG, Hall CM, Goldhaber P. Ibuprofen: an inhibitor of

alveolar bone resorption in beagles. J Periodontal Res 1988:

23: 225229.

151. Williams RC, Jeffcoat MK, Howell TH, Rolla A, Stubbs D,

Teoh KW, Reddy MS, Goldhaber P. Altering the progres-

sion of human alveolar bone loss with the non-steroidal

anti-inflammatory drug flurbiprofen. J Periodontol 1989:

60: 485490.

152. Williams RC, Jeffcoat MK, Howell TH, Paquette DW, Rolla

A, Reddy MS, Goldhaber P. Three-year trial of flurbiprofen

treatment in humans: post-treatment period. J Dent Res

1991: 76: 1617(abstract).

153. Williams CS, Mann M, DuBois RN. The role of cyclooxy-

genases in inflammation, cancer, and development.

Oncogene 1999: 18: 79087916.

154. Xie W, Chipman JG, Robertson DL, Erikson RL, Simmons

DL. Expression of a mitogen-responsive gene encoding

prostaglandin synthase is regulated by mRNA splicing.

Proc Natl Acad Sci U S A 1991: 88: 26922696.

155. Yan M, Noguchi K, Ruwanpura SM, Ishikawa I. Cyclo-

oxygenase-2-dependent prostaglandin (PG) E2 downreg-

ulates matrix metalloproteinase-3 production via EP2/EP4subtypes of PGE2 receptors in human periodontal liga-

ment cells stimulated with interleukin-1a. J Periodontol2005: 76: 929935.

156. Yoshida K, Oida H, Kobayashi T, Maruyama T, Tanaka M,

Katayama T, Yamaguchi K, Segi E, Tsuboyama T, Mats-

ushita M, Ito K, Ito Y, Sugimoto Y, Ushikubi F, Ohuchida S,

Kondo K, Nakamura T, Narumiya S. Stimulation of bone

formation and prevention of bone loss by prostaglandin E

EP4 receptor activation. Proc Natl Acad Sci U S A 2002: 99:

45804585.

157. Yucel-Lindberg T, Ahola H, Nilsson S, Carlstedt-Duke J,

Modeer T. Interleukin-1b induces expression of cyclo-oxygenase-2 mRNA in human gingival fibroblasts.

Inflammation 1995: 19: 549560.

158. Yucel-Lindberg T, Nilsson S, Modeer T. Signal transduc-

tio

peran Cyclooxigenase 2 dan Prostaglandin E2 pada penyakit periodontal

Documents

Transcript of peran Cyclooxigenase 2 dan Prostaglandin E2 pada penyakit periodontal