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Signaling Pathways Regulating IL-1-induced COX-2 Expression

¹ Department of Oral and Maxillofacial Surgery, Graduate School of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; and
² Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science and Station for Collaborative Research, Kyushu University, Fukuoka, Japan

^* corresponding author, yasu{at}dent.kyushu-u.ac.jp

	ABSTRACT

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Interleukin-1(IL-1) stimulates the production of prostaglandin E₂ (PGE₂) in odontogenic keratocyst fibroblasts. However, the signaling pathways remain obscure. In this study, we investigated IL-1signaling pathways that regulate cyclooxygenase-2 (COX-2) expression in odontogenic keratocyst fibroblasts. IL-1increased the expression of COX-2 mRNA and protein, and PGE₂ secretion in the fibroblasts. IL-1increased the phosphorylation of extracellular signal-regulated protein kinase-1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK). PD-98059, SB-203580, SP-600125, and PDTC—which are inhibitors of ERK1/2, p38, JNK, and nuclear factor-B (NF-B), respectively—attenuated the IL-1-induced COX-2 mRNA expression and activated protein kinase C PGE₂ secretion. IL-1(PKC), and PKC inhibitor staurosporine inhibited IL-1-induced phosphorylation of ERK1/2, p38, and JNK, and decreased IL-1-induced COX-2 mRNA expression. Thus, in odontogenic keratocyst fibroblasts, IL-1may stimulate COX-2 expression both through the PKC-dependent activation of ERK1/2, p38, and JNK signaling pathways, and through the NF-B cascade.

KEY WORDS: cyclooxygenase-2 • prostaglandin E₂ • interleukin-1 • odontogenic keratocyst • fibroblasts

	INTRODUCTION

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Interleukin-1 (IL-1) is one of the multifunctional pro-inflammatory cytokines. IL-1is strongly expressed in the epithelial cells of odontogenic keratocysts (Meghji et al., 1992; Kubota et al., 2001; Ninomiya et al., 2002). Recently, it has been shown that IL-1 stimulates the production of prostaglandin E₂ (PGE₂) in mesenchymal cells, including odontogenic keratocyst fibroblasts (Mifflin et al., 2002; Yang et al., 2002; Miyaura et al., 2003; Oka et al., 2005). PGE₂ stimulates osteoclastogenesis by increasing the expression of receptor activation of nuclear factor-B ligand (RANKL) (Oka et al., 2005). Therefore, the expression of IL-1 may play a crucial role in odontogenic keratocyst outgrowth in the jaws.

PGE₂ synthesis requires conversion of arachidonic acid to prostaglandin H₂, by either cyclooxygenase (COX)-1 or COX-2. COX-1 is expressed constitutively in most cells, while COX-2 is usually undetectable under normal conditions, and its expression is increased by pathological stimulation (Vane, 1994). The regulation of COX-2 expression, therefore, is pharmacologically important for PGE₂ synthesis. There are two types of IL-1 binding receptors, type I receptor (IL-1RI) and type II receptor (IL-1RII). The IL-1RI transduces a signal, whereas the IL-1RII does not, but acts as a decoy receptor. When IL-1 binds to IL-1RI, IL-1 leads to activation of two transcription factors, nuclear factor-B (NF-B) and activator protein-1 (AP-1), through the activation of mitogen-activated protein kinases (MAPKs), such as p38 and c-Jun N-terminal kinase (JNK) (Ninomiya-Tsuji et al., 1999). It has been shown that the IL-1-mediated transcription of COX-2 is regulated by many factors, such as extracellular signal-regulated protein kinase (ERK) (Mifflin et al., 2002), p38 (Mifflin et al., 2002; Yang et al., 2002), NF-B signaling pathway (Mifflin et al., 2002; Yang et al., 2002; Catley et al., 2003), and protein kinase C (PKC) (Lin et al., 2000; Molina-Holgado et al., 2000; Mifflin et al., 2002; Di Mari et al., 2003). However, the signaling pathways of IL-1-induced COX-2 expression are very complicated. Therefore, it is important to clarify the signaling process of the IL-1-mediated COX-2 expression in odontogenic keratocysts, to regulate IL-1-dependent outgrowth of the cysts.

The goal of this study was to clarify the signaling pathways mobilized by IL-1 in COX-2 expression in odontogenic keratocyst fibroblasts.

	MATERIALS & METHODS

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Materials
Recombinant human interleukin-1 (rhIL-1) was supplied courtesy of Dainippon Pharmacy Co. (Osaka, Japan). SB203580, PD98059, SP600125, and staurosporine were purchased from BIOMOL Research Laboratories Inc. (Plymouth Meeting, PA, USA). Phorbol 12-myristate 13-acetate (PMA) and PDTC were purchased from Sigma (St. Louis, MO, USA). Non-specific rabbit IgG was purchased from Nichrei Co. (Tokyo, Japan).

Cell Culture
Odontogenic keratocyst fibroblasts were isolated from biopsied odontogenic keratocyst tissues obtained from patients admitted to Kyushu University Dental Hospital, under institutionally approved protocols, after the patients gave informed consent, as described previously (Kubota et al., 2000, 2002). The cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM, Sigma Chemical Co., St. Louis, MO, USA) containing 10% heat-inactivated fetal calf serum (FCS) and antibiotics (100 IU/mL penicillin and 100 µg/mL streptomycin), under a 95% air, 5% CO₂ atmosphere at 37°C. The confluent cells were pre-incubated in serum-free DMEM for 12 hrs at 37°C, and then incubated with fresh serum-free DMEM in the presence or absence of rhIL-1. In some experiments, the cells were pre-treated with protein kinase inhibitors before incubation with fresh serum-free DMEM.

Immunohistochemistry
Immunohistochemical staining for COX-2 was performed on paraffin sections as described previously (Kubota et al., 2001; Ninomiya et al., 2002). Briefly, the deparaffinized and rehydrated sections (4 µm in thickness) were treated with 0.3% hydrogen peroxide (H₂O₂) in 96% methanol for 30 min to block endogenous peroxidase activity. Then, the sections were treated with normal serum for 1 hr to eliminate any non-specific binding of conjugated secondary antibodies, before incubation with polyclonal anti-human COX-2 antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) overnight at 4°C. Subsequently, the sections were incubated with the secondary antibody for 1 hr at room temperature, and with an avidin-biotin-peroxidase complex reagent (DakoCytomation Inc., Carpinteria, CA, USA) for 45 min. As negative controls, the primary antibody was substituted with normal serum at the same dilution.

Western Immunoblotting
Cells were homogenized in sodium dodecyl sulfate (SDS)-sample buffer containing 5% SDS, 0.4 M Tris-HCl (pH 6.8), 30% sucrose, and 0.1 M 2-mercaptoethanol. Samples were run on 12% SDS-polyacrylamide gels, and transferred onto nitrocellulose paper at 60 V for 5 hrs as described previously (Kubota et al., 2000, 2002; Oka et al., 2005). The nitrocellulose paper was incubated with 5% bovine serum albumin in TBST [150 mM NaCl, 10 mM Tris-HCl (pH 8.0), 0.05% Tween-20, and 0.02% NaN₃] for 1 hr, and incubated with a 1:200 dilution of anti-human COX-2 antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) or a 1:400 dilution of polyclonal antibody against phospho-ERK1/2, phospho-p38 MAPK, and phospho-JNK (Cell Signaling Technology Inc., Beverly, MA, USA). The nitrocellulose paper was developed with the Phototope-HRP Western Detection System (Cell Signaling Technology Inc., Beverly, MA, USA). The images of immunostained nitrocellulose blots were analyzed by Chemi Doc XRS-J software (Bio-Rad Laboratory, Richmond, CA, USA), and the relative amounts of phospho-ERK1/2, -p38 MAPK, -JNK were calculated by normalization to the amount of elF4E.

Reverse-transcriptase/Polymerase Chain-reaction (RT-PCR)
Total RNA was extracted from cells by means of the Trizol reagent, according to the manufacturer’s protocol (Gibco/BRL, Gaithersburg, MD, USA). First-strand cDNA was synthesized from 3 µg total RNA, and PCR amplification was performed with the use of 25 µL of cDNA reaction mixture, as described previously (Kubota et al., 2002; Oka et al., 2005). The specific primers for COX-2 were 5'-TTCAAATGAGATTGTGGG AAAAT-3' (upstream) and 5'-AGATCATCTCTGCCTGAG TATCTT-3' (downstream) (Bradbury et al., 2003). The cDNA amplification was carried out with a cycle program at 94°C for 60 sec, at 56°C for 45 sec, and at 72°C for 120 sec, followed by a final extension step at 72°C for 10 min. The specific primers for ß-actin were 5'-GTGGGGCG CCCCAGGCACCA-3' (upstream), and 5'-CTCCTTAATGTCACGCAC GATTTC-3' (downstream) (Kubota et al., 2002; Oka et al., 2005). The amplification was carried out with a cycle program at 94°C for 60 sec, at 65°C for 30 sec, and at 72°C for 45 sec, followed by a final extension step at 72°C for 10 min. PCR products were run on 1.8% agarose gels, and detected by ethidium bromide staining. The images of the gels were captured by a computer system, and the relative amounts of COX-2 mRNA were calculated by normalization with the amount of ß-actin mRNA (Kubota et al., 2002; Oka et al., 2005).

Measurements of Ins(1,4,5)P₃
We measured inositol 1,4,5-triphosphate [Ins(1,4,5)P₃] by a competitive binding assay, using [³ H] Ins(1,4,5)P₃, as described previously (Takeuchi et al., 2000). Briefly, after the stimulation of cells (1.5 x 10⁶ cells) was stopped by 5% trichloroacetic acid, the cell suspension was centrifuged at 15,000 g for 20 min. Water-saturated diethyl ether was added to the supernatant, and the upper water phase was collected. Remaining diethyl ether in the samples was evaporated under N₂ gas. Then, the samples were neutralized to pH 7.5 with 1 N NaOH. Rat brain microsomes were prepared as Ins(1,4,5)P₃ binding protein. The final pellet was suspended in a homogenizing buffer [50 mM Tris-HCl (pH 8.3) and 2 mM EDTA] at a protein concentration of 20–40 mg/mL. The aliquots of neutralized samples were incubated with rat brain microsome and [³ H]Ins(1,4,5)P₃ in 50 mM Tris-HCl (pH 8.3) and 2 mM EDTA for 15 min on ice, and the radioactivity of the [³ H]Ins(1,4,5)P₃ binding was assayed.

Measurements of PGE₂ and PKC Activity
The concentrations of PGE₂ (Assay Designs Inc., Ann Arbor, MI, USA) and activity of PCK (Stressgen, Victoria, Canada) were measured by means of an enzyme immunoassay kit according to the manufacturer’s instructions (Oka et al., 2005). We used a group of serially diluted standard samples of PGE₂ or PKC to generate the standard curves. The assays could measure PGE₂ and PCK activity in the range from 7.81 pg/mL to 1000 pg/mL, and from 2 ng to 50 ng, respectively. Absorbance was measured at 450 nm by means of a microplate reader (Colona Electric, Ibaragi, Japan).

Statistical Analysis
Data are expressed as mean ± SD. The Mann-Whitney U-test was used for statistical analyses, and p values < 0.05 were considered significant.

	RESULTS

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Strong expression of COX-2 was detected immunohisto-chemically in the subepithelial layer fibroblasts of odontogenic keratocysts (Fig. 1A). To examine the effect of IL-1 on COX-2 expression in the fibroblasts, we determined the expression of COX-2 mRNA in fibroblasts isolated from odontogenic keratocysts. When the fibroblasts were incubated with various concentrations of rhIL-1, the expression of COX-2 mRNA was increased in a dose-dependent manner (0.01 nM-1 nM). The expression of COX-2 mRNA was significantly increased to 5.3 ± 0.5 (n = 4) times the control by 0.1 nM rhIL-1. The rhIL-1-induced expression of COX-2 mRNA was increased maximally within 3 hrs, and was sustained for up to 12 hrs (Figs. 1B, 1C). Expression of COX-2 was also increased 1.6 ± 0.3 (n = 4) times the control by 0.1 nM rhIL-1 (Fig. 1D).

View larger version (20K): [in this window] [in a new window]   Figure 1. Effect of IL-1 on the expression of COX-2 in odontogenic keratocyst fibroblasts. (A) A representative immunohistochemical staining for COX-2 in a section of an odontogenic keratocyst. Subepithelial layer fibroblasts were positively stained with anti-COX-2 antibody (arrowheads). Scale bar: 12 µm. (B,C) Fibroblasts (4 x 104 cells/cm2) were incubated in the absence (Co) or presence of various concentrations of rhIL-1 for 6 hrs (B), or were incubated with 0.1 nM rhIL-1 for various times (C). The expression of COX-2 mRNA was measured as described in "MATERIALS & METHODS". The amounts of COX-2 mRNA in the control were normalized as 1.0. Vertical bars indicate mean ± SD (n = 3). * Significant difference at p < 0.05. (D) Fibroblasts were incubated in the absence or presence of 0.1 nM rhIL-1 for 12 hrs, and the aliquots of cell lysates were subjected to Western immunoblotting for COX-2, as described in "MATERIALS & METHODS".

View larger version (32K): [in this window] [in a new window]   Figure 2. Effects of IL-1 on the phosphorylation of ERK1/2, p38, and JNK in odontogenic keratocyst fibroblasts. Fibroblasts (4 x 104 cells/cm2) were incubated with 0.1 nM rhIL-1 for various intervals (A,B,C), or with various concentrations of rhIL-1 for 10 min (D,E) or 20 min (F) at 37°C. Western immunoblotting for phospho-ERK1/2 (A,D), phospho-p38 (B,E), and phospho-JNK (C,F) was performed as described in "MATERIALS & METHODS". The values were normalized to the amounts of the control. Vertical bars indicate mean ± SD (n = 3). * Significant difference at p < 0.05.

View larger version (25K): [in this window] [in a new window]   Figure 3. Effects of inhibitors for MAPKs and NF-B on IL-1-induced expression of COX-2 mRNA and secretion of PGE2 in odontogenic keratocyst fibroblasts. Fibroblasts (4 x 104 cells/cm2) were incubated with 20 µM PD-98059, 20 µM SB-203580, 40 µM SP-600125, and 20 µM PDTC for 1 hr, and then incubated with 0.1 nM rhIL-1 for 6 hrs (A) or 24 hrs (B) at 37°C. (A) The expression of COX-2 mRNA was measured as described in "MATERIALS & METHODS". (B) The concentration of PGE2 in the culture media was measured as described in "MATERIALS & METHODS". The values were normalized to the concentration of the control. Vertical bars indicate mean ± SD (n = 3). * Significant difference at p < 0.05.

View larger version (28K): [in this window] [in a new window]   Figure 4. PKC-dependent COX-2 mRNA expression and MAPKs phosphorylation in odontogenic keratocyst fibroblasts. (A) Fibroblasts (1.5 x 106 cells) were incubated without (Co) or with 0.1 nM rhIL-1 (IL-1) for 30 sec at 37°C. The amounts of Ins(1,4,5)P3 in the cells (n = 4) were measured as described in "MATERIALS & METHODS". (B) Fibroblasts (4 x 104 cells/cm2) were stimulated with 0.1 nM rhIL-1 for 10, 30, and 60 min. Then, the activity of PKC for the cells (n = 3) was measured as described in "MATERIALS & METHODS". Vertical bars indicate mean ± SD. * Significant difference at p < 0.05. (C) Fibroblasts (4 x 104 cells/cm2) were stimulated with 0.1 nM rhIL-1 (lanes 2,3), 0.01% DMSO (lane 4), or 1 µM PMA (lane 5,6) for 6 hrs after pre-incubation without (lanes 1,2,4,5) or with (lanes 3,6) 2 µM staurosporine for 1 hr at 37°C. Then, the expression of COX-2 mRNA was measured as described in "MATERIALS & METHODS". (D) Fibroblasts (4 x 104 cells/cm2) were pre-incubated in the absence (lanes 1,2) or presence (lane 3) of 2 µM staurosporine for 1 hr at 37°C. The cells were then stimulated with 0.1 nM rhIL-1 (lanes 2,3) for 10 min for measurement of the phosphorylation of ERK1/2 and p38, or for 20 min for measurement of the phosphorylation of JNK. The aliquots of cell lysates were subjected to Western immunoblotting as described in "MATERIALS & METHODS".

	DISCUSSION

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IL-1 activates tumor necrosis factor receptor-associated factor 6 (TRAF6), which stimulates TGFß-activated kinase 1 (TAK1). TAK1 mediates the activation of MAPKs such as p38 and JNK, and of NF-B (Ninomiya-Tsuji et al., 1999). In this study, we showed that IL-1 induced phosphorylation of p38 and JNK in odontogenic keratocyst fibroblasts in culture, and that the inhibitors for p38 and JNK attenuated the IL-1-induced expression of COX-2 mRNA and PGE₂ production. An interesting finding was that IL-1 also induced phosphorylation of ERK1/2 in the fibroblasts, and that the inhibitors for ERK1/2 attenuated the IL-1-induced expression of COX-2 mRNA and PGE₂ production. It has been reported that IL-1 did not activate ERKs in human glomerular mesangial cells (Uciechowski et al., 1996), while ERKs were activated by IL-1, depending on focal adhesion establishment (MacGillivray et al., 2000). Therefore, participation of ERKs in IL-1-induced COX-2 expression might be different in cell types and/or cell culture conditions. A specific inhibitor for NF-B also inhibited the IL-1-induced expression of COX-2 mRNA and PGE₂ production. These results are consistent with findings reported previously for other cell types (Mifflin et al., 2002; Yang et al., 2002; Catley et al., 2003). Thus, in odontogenic keratocyst fibroblasts, IL-1 may increase COX-2 expression both through ERK1/2, p38, and JNK signaling pathways, and through the NF-B cascade.

In this study, IL-1 increased the production of Ins(1,4,5)P₃ and activated PKC in odontogenic keratocyst fibroblasts, presumably by activation of phospholipase C. It has been shown that activation of PKC is involved in IL-1-induced COX-2 expression, and phorbol ester stimulates COX-2 expression (Lin et al., 2000; Molina-Holgado et al., 2000; Mifflin et al., 2002; Yang et al., 2002; Di Mari et al., 2003). PKC is divided into three classes, based on primary structure and biochemical properties, conventional PKC isotype (cPKC), novel PKC isotype (nPKC), and atypical PKC isotype (aPKC). Both cPKC and nPKC contain diacylglycerole (DAG) and phorbol ester binding domains, while aPKC lacks the DAG and phorbol ester binding domains. In this study, we showed that PMA activated the expression of COX-2 mRNA, and the PKC inhibitor staurosporine attenuated both the phorbol ester-induced and IL-1-induced expression of COX-2 mRNA. Since neither PMA nor staurosporine affects aPKC, activation of cPKC and/or nPKC may be involved in IL-1-induced expression of COX-2 mRNA in odontogenic keratocyst fibroblasts. It has been reported that, in human intestinal myofibroblasts, aPKC was involved in IL-1-induced COX-2 expression (Di Mari et al., 2003). Therefore, IL-1 might activate the different types of PKC, depending on cell types or species. The cross-talk among PKC, MAPKs, and NF-B in IL-1-induced COX-2 expression has been obscure. In this study, staurosporine inhibited the IL-1-induced phosphorylation of ERK1/2, p38, and JNK. Taken together, our results suggest that PKC is a critical upstream mediator required for the activation of MAPK pathways in COX-2 expression in odontogenic keratocyst fibroblasts.

In conclusion, the results of this study demonstrate that ERK1/2, p38, and JNK signaling pathways, as well as the NF- B cascade, are involved in IL-1-induced COX-2 gene expression in odontogenic keratocyst fibroblasts. In addition, PKC may regulate COX-2 expression by mediating phosphorylation of the MAPKs in the cells.

	ACKNOWLEDGMENTS

 
This work was supported by Grants-in-Aid from the Ministry of Education of Japan (Nos. 15592117, 18592188).

Received February 2, 2006; Last revision August 1, 2006; Accepted October 19, 2006

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