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Force-induced IL-8 from Periodontal Ligament Cells Requires IL-1β
A. Maeda1,
K. Soejima1,
K. Bandow2,
K. Kuroe1,
K. Kakimoto2,
S. Miyawaki1,
A. Okamoto1 and
T. Matsuguchi2,*
1 Department of Orthodontics, and
2 Department of Biochemistry and Molecular Dentistry, Field of Developmental Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan
Correspondence: * corresponding author, tmatsugu{at}denta.hal.kagoshima-u.ac.jp
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ABSTRACT
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During orthodontic tooth movement, mechanical stresses induce inflammatory reactions in the periodontal ligament (PDL). We hypothesized that chemokines released from PDL cells under mechanical stress regulate osteoclastogenesis, and investigated the profiles and mechanisms of chemokine expression by human PDL cells in response to mechanical stress. In vitro, shear stress and pressure force rapidly increased the gene and protein expressions of IL-8/CXCL8 by PDL cells. Consistently, amounts of IL-8 in the gingival crevicular fluid of healthy individuals increased within 2 to 4 days of orthodontic force application. The PDL cells constitutively expressed low levels of IL-1β, which were not further increased by mechanical stress. Interestingly, neutralization of IL-1β abolished IL-8 induction by mechanical stresses, indicating that IL-1β is essential for IL-8 induction, presumably though autocrine or paracrine mechanisms. Finally, experiments with signal-specific inhibitors indicated that MAP kinase activation is essential for IL-8 induction.
Key Words: orthodontics • IL-8 • IL-1β • periodontal ligament cell • mechanical stress
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INTRODUCTION
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The early phase of orthodontic load is transduced into the periodontal ligament (PDL). Several lines of evidence have indicated that PDL cells respond to the mechanical load and regulate the resorption and formation of bone matrix by signaling to the surrounding cells (Davidovitch, 1991; Shimizu et al., 1994, 1998; Long et al., 2001). Notably, PDL cells under mechanical stress synthesize cytokines and growth factors, which may regulate osteoclast functions (Davidovitch, 1991; Long et al., 2001). Various cytokines, such as interleukin (IL)-1β, IL-6, interferon- , and tumor necrosis factor- (TNF-), were reported to be involved in orthodontic tooth movement in animal and human studies (Davidovitch, 1991; Lowney et al., 1995; Uematsu et al., 1996).
Chemokines form a family of structurally related chemoattractant proteins. In general, CC chemokines (including MCP-1, MIP-1, and RANTES) and CXC chemokines (including IL-8) are potent chemoattractants for monocytes and neutrophils, respectively. Chemokines are produced by various cell types in response to bacterial and viral products and physical damage to the tissue. In a rat orthodontic model, MCP-1, RANTES, and MIP-2 expressions have been reported to be significantly increased (Alhashimi et al., 1999).
We hypothesized that chemokines released from PDL cells under mechanical stress may regulate the metabolism of the surrounding bone matrix. The goals of this study were: (1) to examine the gene and protein expression profiles of chemokines in human PDL cells under shear stress and pressure force; (2) to measure chemokine concentrations in the gingival crevicular fluid (GCF) of healthy individuals stimulated by orthodontic force; and (3) to analyze the molecular mechanisms of chemokine expression in human PDL cells.
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MATERIALS & METHODS
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Reagents
Specific inhibitors of p38 kinase (SB203580), JNK (SP600125), and ERK (U0126)/NF- B (MG132) were obtained from Santa Cruz Biotech (Santa Cruz, CA, USA), BIOMOL international, L.P. (Plymouth Meeting, PA, USA), and CALBIOCHEM (San Diego, CA, USA), respectively. The ELISA kit for IL-8 was obtained from Biosource International (Camarillo, CA, USA). The ELISA kits for MIP-1 and RANTES, and a neutralizing anti-IL-1β monoclonal antibody (500-M01B) were obtained from PeproTechEC, Ltd. (London, UK).
Human PDL Cells
To exclude the intermixture of gingivae and dental pulp, we obtained PDL exclusively from the middle of tooth roots extracted for orthodontic reasons. Ligament samples were then cultured in -MEM with 10% FBS, and the PDL cells were used for experiments after 3 or 4 passages. The protocol was reviewed and approved by the Kagoshima University School of Dentistry Research Ethics Committee, and informed consent was obtained from all participants.
Shear Stress Application by Pulsating Fluid Flow
Shear stress was applied with a flow apparatus as previously described (Klein-Nulend et al., 1995). Briefly, PDL cells were plated onto 50 µg/mL poly-L-lysine-pre-coated (Sigma, St. Louis, MO, USA) glass slides at 5 x 105 cells/slide and incubated in 15 mL -MEM with 10% FBS until confluence. The pulsating flow was applied at 5 Hz for 30 min, generating a shear stress of 0.6 ± 0.3 Pa. The shear stress at this magnitude has been demonstrated to be sufficient to induce significant nitric oxide (NO) responses in both mouse bone cells (Bakker et al., 2001) and human PDL cells (van der Pauw et al., 2000). Longer treatments of the same magnitude did not induce any further responses. During experiments, all components were placed at 37°C, and the reservoir was connected to a gassing system that maintained a humidified atmosphere of 5% CO2 in air.
Application of Pressure Force by Centrifugation
Confluent PDL cell culture dishes were centrifuged at 10 g/cm2 (475 rpm) for 20 min. The pressure force of 10 g/cm2 was chosen because it mimics clinical orthodontic force (Redlich et al., 2004), and was more effective than weaker (3 g/cm2) and stronger (30 g/cm2) pressure forces in the preliminary experiments (data not shown). Longer treatments of the same magnitude did not induce any further responses.
Real-time Polymerase Chain-reaction (PCR) Assay
Quantitative real-time PCR was performed with SYBR® Green I (CAMBREX, Rockland, ME) in RG-2000 (Corbett Research, Mortlake, NSW, Australia). The primer sequences were: IL-8 forward, ATGACTTCCAAGCT GGCCGTGGCT, reverse, TCTC AGCCCTCTTCAAAAA CTTCT (292 bp); MIP-1 forward, CATCACTTGCTGCTGACACG, reverse, TGTGGAATCTGCC GGGAG (63 bp); RANTES forward, TACACCAGTGGC AAGTGCTC, reverse, GAAGCCT CCCAAGCTAGGAC (199 bp); MCP-1 forward, CTGCCCTTG CTGTCCTCCTCTG, reverse, CTGCCGGCTTCGCTTGGTTA (297 bp); IL-1β forward, GGCAGAAAGGGAACAGAAA GG, reverse, AGTGAG TAGGAGAGGTGAGAGAGG (200 bp); and GAPDH forward, CATCACCATCTTCCAGGAGC, reverse, CATGAGTCCTT CCACGATACC (307 bp). Annealing temperature was 55°C (GAPDH, IL-8, RANTES) or 58°C (MIP-1, MCP-1, IL-1β).
Western Blotting
Cells underwent lysis in RIPA buffer (50 mM Tris-HCl, 150 mM NaCl, 2 mM EDTA, 1% Triton X-100, 0.5% sodium deoxycholate, 0.1% SDS, pH 7.5). The Western blotting procedure was previously described (Matsuguchi et al., 2003).
Gingival Crevicular Fluid (GCF) Collection
Ten healthy individuals (seven females and three males, age range from 23 to 30 yrs; mean, 26.2 ± 2.3), who gave written informed consent, were included in the study, which was approved by the Ethics Committee of Research on Human Beings of Kagoshima University. They met the following criteria: good general health; no antibiotic therapy within the past 6 mos; no use of anti-inflammatory drugs in the month preceding the study; and good periodontal health, with generalized probing depths  3 mm, gingival index = 0, and PCR 20%. The maxillary right canine was moved in the mesial direction by means of 3 elastic modules (3M Unitek, Monrovia, CA, USA) inserted interdentally from the maxillary right first premolar to the right second molar. GCF was collected from the mesial gingival crevice of the canine by 2 paper strips and was extracted in PBS as previously described (Kakimoto et al., 2002).
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RESULTS
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Chemokine Expression in PDL Cells Induced by Shear Stress and Pressure Force
PDL cells isolated from the tooth roots of five orthodontic patients were exposed to shear stress and pressure force, and mRNA expression for 4 chemokines (IL-8, MIP-1, RANTES, and MCP-1) was quantified by real-time PCR. Two typical results (cell lines 1 and 2) are shown (Figs. 1A , 2A). PDL lines constitutively expressed small amounts of IL-8, MIP-1, and RANTES mRNA. MCP-1 mRNA was undetectable at any time-point. IL-8 mRNA significantly increased at 1.5 or 2.5 hrs, and remained elevated until 6.5 hrs after each treatment in all PDL lines. MIP-1 mRNA was significantly decreased by shear stress and temporarily increased by pressure force (at 2.5 hrs) in 1 cell line (line 1), but remained unchanged in the other (line 2) (Figs. 1Ab, 2Ab). Some variations were observed for RANTES mRNA after shear stress and pressure treatments in both PDL cell lines (Figs. 1Ac, 2Ac), but the fold differences were much less than those for IL-8 mRNA.
IL-8 protein concentrations in culture supernatants gradually increased without stimulation (Figs. 1B , 2B), which is consistent with the constitutive low-level IL-8 mRNA expression in PDL cells (Figs. 1Aa, 1Ba, bottom panels). With pulsating fluid flow and centrifugation treatments, IL-8 concentrations were significantly higher than in unstimulated control samples at 24 and 48 hrs. The concentrations of MIP-1 and RANTES were below detection levels at any time-point (data not shown).
IL-8 Secretion in Orthodontic Tooth Movement
To explore IL-8 secretion by clinical orthodontic force, we moved the maxillary canines of 10 healthy individuals in a mesial direction by means of elastic bands. There were no statistically significant differences in the probing depth, gingival index, and GCF volume. We determined the total IL-8 content in each GCF sample by multiplying IL-8 concentration by GCF volume. Various amounts (from 20 to 65 pg) of IL-8 were detected in the GCF of each participant at day 0 (Fig. 3). In nine out of ten participants, total IL-8 in GCF increased within 2–4 days after load application (Fig. 3).
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Figure 3. IL-8 amounts in GCF samples of individuals with orthodontic force application. GCF was sampled from the mesial gingival crevice of each experimental maxillary canine at indicated times before and after the application of elastic modules. The concentration of IL-8 in GCF was measured by ELISA as described in MATERIALS & METHODS.
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Involvement of IL-1β in Mechanical Stimuli-induced IL-8 Expression in PDL Cells
To assess the role of IL-1β, we first analyzed IL-1β gene expression in 2 PDL cell lines in response to mechanical stimuli by real-time PCR. The PDL cells constitutively expressed a low-level IL-1β mRNA, but stimulation with either shear stress or pressure force did not increase IL-1β mRNA (Fig. 4A). In contrast, IL-1β mRNA was decreased moderately but significantly in both PDL cell lines by shear stress, and in 1 PDL cell line by pressure force. We then pre-treated PDL cells with a neutralizing anti-IL-1β antibody, and analyzed IL-8 mRNA induction by mechanical stimuli. Neutralization of IL-1β abrogated the inducible expression of IL-8 mRNA (Fig. 4B).
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Figure 4. Involvement of IL-1β and MAPK activation in the IL-8 expression by PDL cells. (A) Two lines of PDL cells (lines 1 and 2) were stimulated by pulsating fluid flow (a) or centrifugal force (b), then incubated for 1.5–6.5 hrs in fresh medium for total RNA collection. IL-1β mRNA levels were quantified by real-time PCR. Vertical bars indicate mean ± SD (n = 3). *Indicates significant (p < 0.05) difference as compared with untreated cells, calculated by t test. (B) PDL cells (line 1) were incubated in medium supplemented with anti-IL-1β (5 ng/mL) or the control antibody (5 ng/mL) for 0.5 hr before stimulation. After stimulation with pulsating fluid flow (a) or centrifugation (b), PDL cells were incubated for 3.5 hrs (a) or 4.5 hrs (b). IL-8 mRNA levels were quantified by real-time PCR. Vertical bars indicate mean ± SD (n = 3). *Indicates a significant difference (p < 0.05), by t test. (C) Roles of p38 kinase, JNK, ERK, and NF-B on IL-8 expression by PDL cells. PDL cells (line 1) were pre-incubated with various concentrations of each indicated inhibitor for 0.5 hr before stimulation. As the negative control, DMSO was added to the medium. The cells were then stimulated by a pressure centrifugal force, followed by the 4.5-hour incubation in medium before total RNA collection. IL-8 mRNA levels were quantified by real-time PCR, as described in MATERIALS & METHODS. Vertical bars indicate mean ± SD (n = 3). *Indicates a significant difference (p < 0.05), by t test. (D) Effects of specific inhibitors on activated signaling molecules. PDL cells (line 1) were pre-incubated with each indicated inhibitor for 0.5 hr before stimulation. As the negative control, DMSO was added to the medium. The cells were collected immediately after stimulation by a pressure centrifugal force. Cell lysates were analyzed by Western blotting.
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IL-8 Induction by Pressure Force is Dependent on MAP Kinase But Not NF-B Activation
To analyze the downstream signals of the mechanical stimuli leading to IL-8 induction, we pre-treated PDL cells with a specific inhibitor of p38 kinase, JNK, ERK, or NF-B. Specific inhibitors of p38 kinase, JNK, and ERK significantly inhibited IL-8 mRNA induction dose-dependently with pressure force (Fig. 4C). We confirmed that the 3 MAP kinase inhibitors successfully inhibited the phosphorylation of each target kinase induced by pressure (Fig. 4D). In contrast, pressure did not reduce the cytoplasmic content of IB (Fig. 4D), and a specific NF-B inhibitor showed no inhibitory effect (Fig. 4C).
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DISCUSSION
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One of the first reactions to an orthodontic load is the stress-strain alterations within the PDL. In the classic model, compressive stimulus on the roots along the movement direction induces bone resorption, while tension on the other side leads to bone formation (Davidovitch, 1991). When the tooth is loaded, PDL cells are also exposed to fluid shear stress, due to the visco-elastic properties of the PDL (Ferrier and Dillon, 1983). PDL cells also respond to IL-1β (Long et al., 2001) and LPS (Yamaji et al., 1995) by expressing IL-8, and the GCF of persons with periodontal disease contains higher levels of IL-8 and RANTES (Gamonal et al., 2000), indicating that PDL cells are the source of chemokines under certain conditions. The detailed chemokine expression profile of PDL cells by mechanical stress, however, has not been elucidated.
Here, we demonstrated that PDL cells constitutively expressed mRNAs for IL-8, MIP-1, and RANTES, but not MCP-1. Among these chemokines, IL-8 mRNA markedly increased after shear stress and pressure treatments. The fold induction of IL-8 protein was much less than the peak induction of IL-8 mRNA (Figs. 1Aa, 1B, 2Aa, 2B), presumably because IL-8 mRNA induction was only transient after the brief treatments by shear stress and pressure force. It is not likely that this expression profile was due simply to clonal variation, since all 5 PDL cell clones examined showed similar profiles (data not shown).
Pulsating fluid flow is an effective method for the application of shear stress to cells, and has been proven to induce the production of NO and PGE2 from osteocytes (Klein-Nulend et al., 1995) and endothelial cells (Buga et al., 1991). In a previous report, PDL cells, but not gingival fibroblasts, were reported to respond to pulsating fluid flow with significantly elevated NO and PGE2 release, indicating that PDL cells were more sensitive to shear stress than were gingival fibroblasts (van der Pauw et al., 2000).
We found various amounts (from 20 to 65 pg) of IL-8 in the GCFs of healthy participants. More importantly, the amounts of IL-8 in nine out of ten participants increased within 2–4 days of orthodontic force application. Thus, in orthodontic tooth movement, it is reasonable to presume that PDL-derived IL-8 recruits inflammatory cells, which produce pro-inflammatory cytokines, such as TNF-, IL-1, and IL-6, which are known to induce osteoclast differentiation, contributing to alveolar bone destruction (Kobayashi et al., 2000; van’t Hof et al., 2000). Quite recent reports, in contrast, have revealed more direct effects of IL-8 on bone resorption (Bendre et al., 2003, 2005). IL-8 stimulates RANKL expression in osteoblasts without inducing the antagonizing osteoprotegerin. More intriguingly, CXCR1 (the IL-8 receptor) has been detected on the surfaces of osteoclasts and their progenitors, indicating that IL-8 may directly stimulate osteoclastogenesis without the involvement of RANKL. Thus, it is possible that increased IL-8 secretion from PDL cells by orthodontic load may directly activate local osteoclastogenesis.
The abrogation of IL-8 induction by neutralizing IL-1β indicated an essential role of IL-1β in mechano-stress-mediated IL-8 expression. Interestingly, however, under our experimental conditions, IL-1β mRNA in PDL cells was not increased by either shear stress or pressure force. Thus, the constitutive low-level expression of IL-1β appears sufficient for IL-8 expression to be responsive to mechanical stimuli. Previous reports indicated that IL-1β production by PDL cells is increased by mechanical strain of high magnitude (Shimizu et al., 1994), whereas equi-biaxial tensile stain of low magnitude inhibits IL-1β production by PDL cells (Long et al., 2001). Thus, mechanical forces may affect IL-1β production by PDL cells in a rather complex manner, depending on the nature and magnitude of the loads. Additionally, MCP-1 mRNA was undetectable in our experimental system, whereas MCP-1 mRNA was reported to be promoted by IL-1β in human PDL cells (Ozaki et al., 1996). This may indicate that the endogenous low-level expression of IL-1β is not sufficient to induce MCP-1 gene expression.
Our results indicated that IL-8 induction in PDL cells required the concomitant presence of 2 signals: one from IL-1β, and the other directly from the mechanical stimulus. IL-8 expression is regulated primarily at the transcriptional level, and its promoter contains functional binding sites for NF-B, C/EBP, and AP-1 (Mukaida et al., 1990; Yasumoto et al., 1992). IL-1β activates ERKs and p38 in various cell types (Fan et al., 2001; Suzuki et al., 2001), and induces IL-8 gene expression through AP-1 and NF-B in human vascular smooth-muscle cells (Jung et al., 2002). In contrast, downstream signals of many mechanical stimuli have not been well-described. A report analyzing human airway smooth-muscle cells indicated that mechanical stretch increased IL-8 transcription through AP-1 and C/EBP via ERK and p38 kinase activations (Mukaida, 2000). In the present study, we found that pressure force rapidly activated ERK, JNK, and p38, but not the NF-B pathway. Consistently, pressure-induced IL-8 expression was inhibited by specific inhibitors for ERK, JNK, and p38 kinase, but not by that for MG-132, indicating that PDL cells require activation of the 3 MAP kinases, but not NF-B, for pressure-induced IL-8 expression.
It should be noted, however, that cell types other than PDL cells may contribute to local IL-8 expression, since IL-8 can be produced by various kinds of cells, including monocytes, epithelial cells, fibroblasts, and endothelial cells. The most likely candidate is gingival fibroblasts, since they have been previously reported to produce IL-8 in response to IL-1β (Yucel-Lindberg and Brunius, 2006).
In summary, we demonstrated that IL-8 is preferably induced by shear stress and pressure force in human PDL cells. Increased IL-8 levels in GCF during orthodontic tooth movement indicated that local IL-8 expression is evident in response to clinical orthodontic loads. Since IL-8 seems to activate osteoclastogenesis through various mechanisms, mechano-stress-induced IL-8 from PDL cells may play an essential role in efficient orthodontic tooth movement.
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ACKNOWLEDGMENTS
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This study was supported by Grants-in-aid for Scientific Research (B) for T.M. and Encouragement of Scientists (B) for K.S. from the Japan Society for the Promotion of Science.
Received for publication February 13, 2006.
Revision received January 17, 2007.
Accepted for publication February 8, 2007.
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Journal of Dental Research, Vol. 86, No. 7,
629-634 (2007)
DOI: 10.1177/154405910708600709
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ABSTRACT
INTRODUCTION
