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Prostaglandin E₂ Regulates Interleukin-1ß-induced Matrix Metalloproteinase-3 Production in Human Gingival Fibroblasts

¹ Periodontology, Department of Hard Tissue Engineering, Graduate School, and ² Centre of Excellence Program for Frontier Research on Molecular Destruction of Tooth and Bone, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8549, Japan;

^* corresponding author, pradeepruwanpura.peri{at}tmd.ac.jp

	ABSTRACT

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Prostaglandin E₂ (PGE₂) exerts its biological actions via EP receptors (EP₁, EP₂, EP₃, and EP₄). In the present study, we investigated whether PGE₂ regulated interleukin (IL)-1ß-induced matrix metalloproteinase (MMP)-3 production in human gingival fibroblasts (HGF) derived from periodontally healthy subjects and diseased patients. In HGF from healthy gingiva, PGE₂ down-regulated IL-1ß-induced MMP-3 production, whereas in HGF from periodontitis patients, PGE₂ enhanced it. Butaprost (an EP₂ agonist) and ONO-AE1-329 (an EP₄ agonist) suppressed IL-1ß-induced MMP-3 production, and 17-phenyl--trinor PGE₂ (an EP₁ agonist) mimicked the PGE₂ effect in HGF from healthy and periodontally diseased tissues, respectively. Analysis of these data suggests that, in HGF from healthy tissue, IL-1ß-induced MMP-3 production is down-regulated by PGE₂ via EP₂ and EP₄ receptors, whereas in cells from periodontally diseased tissue, IL-1ß-induced MMP-3 production is up-regulated via EP₁ receptors. Different regulation of IL-1ß-induced MMP-3 production by PGE₂ between healthy and periodontally diseased tissues may be involved in the pathogenesis of periodontal disease.

KEY WORDS: human gingival fibroblasts • interleukin-1ß • matrix metalloproteinase-3 • prostaglandin E₂ • EP receptors

	INTRODUCTION

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Prostaglandins (PGs), including PGE₂, play numerous roles under physiological and pathological conditions. PGE₂ is thought to be involved in the pathogenesis of periodontal disease, due to its role as a potent stimulator of bone resorption and association with attachment loss (Offenbacher et al., 1993). PGE₂ exerts its biological actions via specific PGE receptors on target cells, and 4 distinct subtypes of PGE receptors-designated EP₁, EP₂, EP₃, and EP₄—have been identified and cloned, each with unique signal transduction mechanisms as a result of coupling to different G proteins (Negishi et al., 1995; Narumiya et al., 1999). EP₁ receptor activation induces elevation of intracellular calcium levels via a poorly characterized mechanism involving G proteins. EP₂ and EP₄ receptors activate adenylate cyclase via stimulatory G protein, and result in elevation of intracellular cAMP levels. Multiple isoforms of EP₃ receptors with different C-terminal tails mediate several signaling pathways, including inhibition and stimulation of adenylate cyclases, activation of phospholipase C, and mobilization of intracellular calcium.

Matrix metalloproteinases (MMPs), including MMP-3 (also called stromelysin-1), are a family of Zn endopeptidases that play a key role in extracellular matrix (ECM) turnover. MMP-3 is known to utilize various ECM proteins as its substrate, including proteoglycan core protein, fibronectin, elastin, laminin, gelatin, and collagen types II, III, IV, V, IX, X, and XI (Birkedal-Hansen, 1993). MMP-3 can activate procollagenase, including proMMP-1 (Murphy et al., 1987). Expression of MMPs, including MMP-3, in periodontal lesions has been demonstrated (Birkedal-Hansen, 1993; Ingman et al., 1994). Cross-sectional study of gingival crevicular fluid (GCF) analysis has revealed that GCF MMP-3 and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels can differentiate between healthy and diseased periodontal sites (Haerian et al., 1995). Furthermore, it has been shown that periodontal pockets with high GCF levels of MMP-3 and TIMP-1 are at significantly higher risk for periodontal disease progression (Alpagot et al., 2001). Human gingival fibroblasts (HGF) are known to secrete MMP-3 in response to stimuli, including IL-1 (Tewari et al., 1994).

However, the regulation of MMP-3 production in periodontal lesions is poorly understood. The present study was undertaken to investigate the effect of PGE₂ on IL-1ß-induced MMP-3 secretion in HGF derived from periodontally healthy subjects and diseased patients. Furthermore, we examined which subtype(s) of PGE₂ receptors were involved in PGE₂ regulation of IL-1ß-induced MMP-3 secretion.

	MATERIALS & METHODS

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Culture of HGF
With informed consent, we obtained gingival biopsies from three periodontally healthy subjects (aged 20, 22, and 37 yrs), who had no sites with clinical attachment loss of greater than 2 mm and exhibited no radiographic bone loss, and from three patients (aged 45, 47, and 61 yrs) affected with severe periodontitis, with clinical probing depth sites of greater than 5 mm and clinical attachment loss of greater than 5 mm, and radiographic evidence of severe bone loss. Our study protocol, including biopsy of gingival tissue, satisfied the ethical standards of Tokyo Medical and Dental University. Fibroblasts which extended from pieces of gingiva were cultured in -minimum essential medium (-MEM) containing 10% fetal bovine serum (FBS) (Bioserum, Victoria, Australia), 100 U/mL penicillin (Sigma Chemical Co., St. Louis, MO, USA), and 100 U/mL streptomycin (Sigma). During their successive passages, cells were cultured at 37°C in a humidified atmosphere with 5% CO₂ in the air. Cells between the fourth and fifteenth passages were used in the experiments.

Cell Stimulation
HGF were seeded in 96-well plates. After confluence, they were serum-starved in -MEM containing 0.5% FBS to reduce the effect of serum on MMP-3 production. After 24 hrs, the cells were treated with IL-1ß (Sigma), PGE₂ (Cascade Biochem LTD, Berkshire, UK), 17-phenyl--trinor PGE₂ (Cayman Chemicals, Ann Arbor, MI, USA), butaprost (a gift from ONO Pharmaceuticals Co. Ltd, Tokyo, Japan), ONO-AE1-329 (a gift from ONO Pharmaceuticals Co. Ltd.), ONO-AP-324 (a gift from ONO Pharmaceuticals Co. Ltd.), indomethacin, dibutyryl cAMP, and forskolin (Wako, Tokyo, Japan), in the combinations and concentrations indicated. Indomethacin was added 30 min prior to stimulation with IL-1ß. Cells were pre-treated with SC51322, an EP₁ receptor antagonist, when indicated. Conditioned medium was collected after 72 hrs of incubation, and stored at -80°C until analysis.

Zymography for Caseinolytic Activity Assay
To determine caseinolytic activity in the culture media, we performed casein zymography. One mg/mL of ß-casein was co-polymerized in the 10% polyacrylamide gel. The conditioned media samples were diluted in loading buffer containing 2% SDS under non-reducing conditions. Diluted samples were subjected to sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) without being boiled, at a constant voltage of 200 V. When the bromophenol blue indicator front reached the bottom of the gel (in approximately 1 hr), electrophoresis was stopped. The gels were subsequently washed in 2.5% Triton-X at room temperature to remove SDS. The gels were then incubated in incubation buffer containing 50 mM Tris HCl, 5 mM CaCl₂, 0.02% NaN₃, 200 mM NaCl, and 0.02% Brij35 (Polyoxyethylene 23 lauryl ether) at 37°C overnight and stained with Coomassie Brilliant Blue R-250.

ELISA for PGE₂ and MMP-3
PGE₂ and MMP-3 levels in the conditioning media collected from IL-1ß-treated HGF were determined by commercially available enzyme-linked immunosorbant assay (ELISA) kits (PGE₂, Amersham Pharmacia Biotech, Buckinghamshire, UK; MMP-3, Dai-ichi Fine Chemicals, Toyama, Japan) according to manufacturer’s instructions.

Statistical Analysis
Data are expressed as the mean ± standard deviation (SD). Data were subjected to one-way analysis of variance (ANOVA), with the StatView program. Fisher’s protected least-significant difference test was used in the post hoc comparison of specific groups.

	RESULTS

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Effect of Indomethacin on IL-1ß-induced MMP-3 and PGE₂ Production in HGF Derived from Healthy Gingiva
To examine the involvement of endogenous prostaglandins on MMP-3 secretion in HGF derived from healthy gingiva stimulated with IL-1ß, we investigated the effect of indomethacin, a cyclooxygenase inhibitor, on MMP-3 production by the cells. IL-1ß alone induced MMP-3 production in a dose- and time-dependent manner (data not shown). It was shown by ELISA analysis that, in these cells, indomethacin significantly increased IL-1ß-induced MMP-3 secretion, although indomethacin completely inhibited IL-1ß-induced PGE₂ secretion (Figs. 1A, 1C). Casein zymography analysis with culture media showed that caseinolytic activities appeared as clear bands at the Mr size of approximately 55 kDa in the samples derived from healthy tissue cells treated with IL-1ß, although no band was detected in the samples from non-stimulated cells. Expression of the bands was completely inhibited by the addition of EGTA and o-phenanthroline, a general metalloproteinase inhibitor (Stix et al., 2001). The 55-kDa proteinase has been shown to be proMMP-3 (Lark et al., 1990; Kapila et al., 1996). Furthermore, we confirmed, by Western blot analysis, that MMP-3 protein was detected at the Mr size of approximately 55 kDa (data not shown). As shown in Fig. 1B, treatment of IL-1ß-stimulated HGF with indomethacin enhanced caseinolytic activities. In casein zymography, the active 45-kDa form of MMP-3 was not observed in any samples.

View larger version (18K): [in this window] [in a new window]   Figure 1. Effect of indomethacin on MMP-3 (A,B) and PGE2 (C) production in IL-1ß-stimulated HGF derived from healthy gingiva. These cells were stimulated with vehicle or 2 ng/mL IL-1ß in the presence or absence of 1 µM of indomethacin for 72 hrs. After incubation, MMP-3 (A) and PGE2 levels (C) and caseinolytic activities (B) in the culture media were evaluated by enzyme-linked immunosorbent assay and casein zymography, as described in MATERIALS & METHODS. Values are mean + SD (n = 4). Data are representative of 3 separate experiments. *Significantly different from control (p < 0.0001). **Significantly different from IL-1ß alone (p < 0.001). #Significantly different from control (p < 0.0001). ##Significantly different from IL-1ß alone (p < 0.001).

View larger version (52K): [in this window] [in a new window]   Figure 2. Effects of PGE2, various EP agonists, or cAMP-elevating agents on MMP-3 levels and activities in IL-1ß-stimulated HGF derived from healthy gingiva. Cells were stimulated with vehicle or 2 ng/mL IL-1ß in the presence of 1 µM indomethacin, with or without various doses of PGE2, 17 phenyl--trinor PGE2, butaprost, and ONO-AE-1329 for caseinolytic activity assay (A,B,C,D), or with or without various doses of PGE2, 1 µM of 17 phenyl--trinor PGE2, 1 µM of butaprost, 1 µM of ONO-AE1-329, 100 µM of dibutyryl cAMP (dbcAMP), and 10 µM of forskolin (FS) for MMP-3 protein level assay (E,F,G,H), for 72 hrs. After incubation, caseinolytic activities and MMP-3 protein levels in the culture media were assayed by casein zymography and enzyme-linked immunosorbent assay, respectively, as described in MATERIALS & METHODS. Values are mean ± SD (n = 4). Data are representative of 3 separate experiments. *Significantly different from indomethacin+1L-1ß (p < 0.05). **Significantly different from indomethacin+1L-1ß (p < 0.0001). ***Significantly different from indomethacin+1L-1ß (p < 0.001). #Significantly different from indomethacin+1L-1ß (p < 0.05). $Significantly different from indomethacin+1L-1ß (p < 0.05). $$Significantly different from indomethacin+1L-1ß (p < 0.005). @Significantly different from indomethacin+1L-1ß (p < 0.0001).

Effect of Indomethacin on IL-1ß-induced MMP-3 and PGE₂ Production in HGF Derived from Periodontally Affected Gingiva
Contrary to the result obtained in HGF derived from healthy tissue, in HGF from periodontally affected tissue, indomethacin significantly inhibited IL-1ß-induced MMP-3 secretion (Fig. 3A). Similarly, casein zymography analysis showed that indomethacin caused an inhibitory effect on IL-1ß-induced caseinolytic activities (Fig. 3B). Indomethacin completely decreased IL-1ß-induced PGE₂ production (Fig. 3C).

View larger version (25K): [in this window] [in a new window]   Figure 3. Effect of indomethacin on MMP-3 (A,B) and PGE2 (C) production in IL-1ß-stimulated HGF derived from periodontally affected tissue. Cells were stimulated with vehicle or 2 ng/mL IL-1ß in the presence or absence of 1 µM of indomethacin for 72 hrs. After incubation, MMP-3 (A) and PGE2 (C) levels and caseinolytic activities (B) in the culture media were evaluated by enzyme-linked immunosorbent assay and casein zymography, as described in MATERIALS & METHODS. Values are mean ± SD (n = 4). Data are representative of 3 separate experiments. *Significantly different from control (p < 0.0001). **Significantly different from IL-1ß alone (p < 0.001). #Significantly different from control (p < 0.0001). ##Significantly different from IL-1ß alone (p < 0.001).

View larger version (23K): [in this window] [in a new window]   Figure 4. Effects of PGE2, 17 phenyl--trinor PGE2, butaprost, and ONO-AE1-329 on production of MMP-3 in IL-1ß-stimulated HGF derived from periodontally affected gingiva. Cells were stimulated with vehicle or 2 ng/mL IL-1ß in the presence of 1 µM indomethacin, with or without various doses of PGE2, 17 phenyl--trinor PGE2, butaprost, and ONO-AE1-329 for caseinolytic activity assay (A,B,C,D), or with or without 1 µM of PGE2, 17 phenyl--trinor PGE2, butaprost, and ONO-AE1-329 for MMP-3 protein level assay (E), for 72 hrs. After incubation, caseinolytic activities and MMP-3 protein levels in the culture media were assayed by casein zymography and enzyme-linked immunosorbent assay, respectively, as described in MATERIALS & METHODS. Values are mean ± SD (n = 4). Data are representative of 3 separate experiments. *Significantly different from indomethacin+IL-1ß (p < 0.0001).

	DISCUSSION

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PGE₂ exerts its biological actions via specific PGE receptors on target cells and, based on ligand-binding selectivity and signaling pathway activation, PGE₂ receptors are classified as EP₁, EP₂, EP₃, and EP₄ subtypes (Negishi et al., 1995; Narumiya et al., 1999). We have previously demonstrated that functional EP₁, EP₂, and EP₄ subtypes of PGE₂ receptors are expressed in HGF (Noguchi et al., 2000). 17-phenyl--trinor PGE₂, a selective EP₁ agonist, up-regulated IL-1ß-stimulated MMP-3 production in both healthy and periodontally affected tissue-derived cells (Figs. 2B, 2F; 4B, 4E). EP₁ receptor activation is linked to elevation of intracellular Ca²⁺ levels. It has been shown that intracellular Ca²⁺ elevation interacts synergistically with protein kinase C (PKC) to induce MMP-3 gene expression (Rodland et al., 1992). Since IL-1ß can induce PKC activation in HGF, it is likely that the intracellular Ca²⁺ increase mediated by EP₁ receptors and PKC activation by IL-1ß synergistically enhanced MMP-3 production in these cells. However, both butaprost (a selective EP₂ agonist) and ONO-AE1-329, a selective EP₄ agonist, down-regulated IL-1ß-stimulated MMP-3 production in HGF derived from healthy tissue, although the agents had no or little effect on IL-1ß-stimulated MMP-3 production in their periodontally affected counterparts (Figs. 2C, 2D, 2G; 4C, 4D, 4E). It has been demonstrated that cAMP can inhibit MMP-3 induction by IL-1 at the transcriptional level in human rheumatoid synovial fibroblasts and uterine cervical fibroblasts, although not in human dermal fibroblasts (Case et al., 1990; Takahashi et al., 1991; Mauviel et al., 1994). EP₂ and EP₄ receptors are linked to intracellular cAMP elevation. Since cAMP-elevating agents including dibutyryl cAMP and forskolin mimicked inhibition of IL-1ß-induced MMP-3 production by PGE₂ in HGF from healthy tissue (Fig. 2H), we suggest that EP₂ and EP₄ receptor activation causes inhibition of IL-1ß-induced MMP-3 production via cAMP-dependent pathways in these cells. The levels of intracellular cAMP in both cell types stimulated with PGE₂, butaprost and ONO-AE1-329, were similar (data not shown), which shows that functional EP₂ and EP₄ receptors were expressed in them. In the present study, we did not investigate why EP₂ and EP₄ receptor activation could not suppress IL-1ß-induced MMP-3 production in HGF from periodontally affected tissue, although EP₂ and EP₄ receptor activation resulted in intracellular cAMP elevation. It is possible, however, that the difference of regulation is further downstream in the EP₂- and EP₄-mediated signaling cascade. From these results, we suggest that PGE₂ down-regulates IL-1ß-stimulated MMP-3 production via EP₂/EP₄ receptors in HGF from healthy tissue, whereas EP₁ receptors are involved in PGE₂ up-regulation of IL-1ß-stimulated MMP-3 production in HGF from periodontally affected cells. Further studies are needed to clarify the mechanism by which PGE₂ differently regulates IL-1ß-induced MMP-3 production in these cells.

MMP-3 expression in periodontal lesions has been demonstrated (Ingman, 1994). Cross-sectional study of gingival crevicular fluid (GCF) analysis has revealed that GCF MMP-3 and TIMP-1 levels can differentiate between healthy and diseased periodontal sites (Haerian et al., 1995). Furthermore, it has been shown that periodontal pockets with high GCF levels of MMP-3 and TIMP-1 are at significantly higher risk for periodontal disease progression (Alpagot et al., 2001). MMP-3 not only utilizes various ECM proteins as its substrate—including proteoglycan core protein, fibronectin, elastin, laminin, gelatin, and collagen types II, III, IV, V, IX, X, and XI (Birkedal-Hansen, 1993)—but also activate procollagenase, including proMMP-1 (Murphy et al., 1987). MMP-3 activates proforms of cytokines like IL-1. Therefore, it is likely that PGE₂ enhancement of IL-1ß-induced MMP-3 production in HGF from diseased tissue is involved in periodontal tissue breakdown. Further studies are necessary to confirm this hypothesis.

In conclusion, we suggest that IL-1ß-induced MMP-3 production is down-regulated by PGE₂ via EP₂ and EP₄ receptors in HGF derived from healthy gingiva, whereas IL-1ß-induced MMP-3 production is up-regulated via EP₁ receptors in HGF from periodontally affected tissue. These data may reflect the heterogeneity of inflammatory responses in healthy and diseased gingiva. Differential regulation of IL-1ß-induced MMP-3 production by PGE₂ in HGF may play critical roles in the regulation of extracellular matrix breakdown in periodontal disease.

	ACKNOWLEDGMENTS

 
This study was supported by a grant from the Centre of Excellence (COE) Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University.

Received May 16, 2003; Last revision December 21, 2003; Accepted December 29, 2003

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