Skip to main content
NCBI home page
Journal of Oral Biology and Craniofacial Research logoLink to Journal of Oral Biology and Craniofacial Research
. 2020 Jun 22;10(4):412–416. doi: 10.1016/j.jobcr.2020.06.005

Vibration synergistically enhances IL-1β and TNF-α in compressed human periodontal ligament cells in the frequency-dependent manner

Sutiwa Benjakul a, Boontarika Unat b, Peungchaleoy Thammanichanon c, Chidchanok Leethanakul b,∗
PMCID: PMC7397387  PMID: 32775184

Abstract

Objectives

To investigate whether mechanical vibration at 30 or 60 Hz combined with compressive force alter IL-1β and TNF-α expression in human periodontal ligament (hPDL) cells.

Methods

hPDL cells isolated from the roots of first premolar teeth extracted from four independent donors were cultured and exposed to vibration (0.3 g, 20 min per cycle, every 24 h for 3 cycles) at 30 or 60 Hz (V30 or V60), 2.0 g/cm2 compressive force for 2 days (CF), or a combination of compressive force and vibration at 30 Hz or 60 Hz (V30CF or V60CF). Quantitative real-time polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assays (ELISAs) were used to determine IL-1β and TNF-α mRNA and protein, respectively.

Results

The levels of IL-1β and TNF-α did not alter in groups V30 and V60. While, they were upregulated in groups CF, V30CF and V60CF. In addition, IL-1β mRNA and TNF-α mRNA and protein were expressed at significantly higher levels in group V30CF compared to CF group. However, IL-1β protein levels between V30CF and CF groups did not reach statistical significance.

Conclusions

30 Hz vibration had the synergistic effects with compressive force on the upregulation of IL-1β mRNA and TNF-α mRNA and protein in PDL cells, while 60 Hz vibration did not have this synergistic effect.

Keywords: Accelerated tooth movement, Biomarkers, Cytokines, Vibratory stimulation

1. Introduction

Vibratory stimulation with low-magnitude, high-frequency (LMHF) has recently been employed as a non-invasive stimulus in device-assisted orthodontic tooth movement. Although a number of in vitro and in vivo studies have attempted to identify how vibration affects tooth movement, the outcomes remain controversial.1,2 Recent animal research suggested that effects of vibration during tooth movement are the inflammation dependent catabolic cascade which has the direct effects on periodontal ligament (PDL), while in the absence of inflammation, it has anabolic effects on the craniofacial skeleton.3 However, in-depth investigations on the effects of vibration remain to be defined, especially at the cellular and molecular levels.

Previously, our in vivo study showed vibration upregulated interleukin (IL)-1β in gingival crevicular fluid (GCF) and increased the tooth movement rate in patients undergoing orthodontic treatment.1 We proposed that PDL cells may play a crucial role in this response. Then we studied the responses of human periodontal ligament (hPDL) cells to vibratory stimulation and discovered that the potent osteoclastogenic factors cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), IL-6, IL-8 and receptor activator of nuclear factor kappa-Β ligand (RANKL) were increased by LMHF vibration. Moreover, combined vibration and compressive force further upregulated the expression of these osteoclastogenic factors in vitro.4, 5, 6, 7 On the other hand, we found that vibration does not have a significant effect on IL-1β, IL-6 and RANKL expressions in osteoblastic cells of human alveolar bone even if in combination with compressive force.8 Based on our previous studies,1,4, 5, 6, 7, 8 we propose that the elevation of IL-1β in patients who received vibration accelerated tooth movement is the responsibility of PDL cells, not human alveolar bone osteoblasts. However, direct effects of vibration on the expression of IL-1β in PDL cells are unknown.

In response to application of orthodontic force, PDL cells release numerous cytokines that regulate alveolar bone remodeling,9 including IL-1β and tumor necrosis factor (TNF)-α, which directly bind to their specific receptors on osteoclast precursor cells to stimulate osteoclast differentiation and activation.10,11 IL-1β and TNF-α also exert indirect paracrine effects by stimulating other surrounding cells to express macrophage colony-stimulating factor (M-CSF) and RANKL, that initiate bone resorption.12 In addition, they are upregulated in human GCF during the early stages of tooth movement,13 with evidence of positive relationships on the magnitude of tooth movement.14 Thus, IL-1β and TNF-α could possibly represent biomarkers of the rate of tooth movement. Although numerous studies have investigated the effects of mechanical force on IL-1β and TNF-α in PDL cells,15, 16, 17 the effects of compressive force in combination with vibratory stimulation on IL-1β and TNF-α have not been investigated in vitro. We propose that vibration upregulates the potent inflammatory cytokines IL-1β and TNF-α in PDL cells, which in turn initiate alveolar bone remodeling.

Although we previously reported PGE2 and RANKL expression were not significantly differently upregulated in PDL cells exposed to different frequencies of vibration (30, 60 and 90 Hz),4 many studies have reported the effects of vibration as frequency dependent.18, 19, 20 In addition, the effects of compressive force in combination with different frequencies of vibration on IL-1β and TNF-α are unknown. We propose that combined vibration and compressive force may upregulate IL-1β and TNF-α in a frequency-dependent manner. Therefore, we investigated the effects of combining mechanical vibration at 30 or 60 Hz with compressive force on IL-1β and TNF-α in hPDL cells.

2. Materials and methods

2.1. Isolation of hPDL cells

Four independent hPDL cell lines were isolated from sound premolar teeth which were extracted from healthy individuals, according to orthodontic treatment planning (2 females, 2 males; 14 to 19-years-old). The protocol was approved by the Prince of Songkla University, Faculty of Dentistry Institutional Ethics Committee Board (EC6003-04-P-LR); signed consent forms were obtained from all participants. The cells were isolated from the tooth at the middle third of the root and immediately cultured in 5% CO2 at 37 °C, in Dulbecco's modified essential medium (DMEM) containing 10% fetal bovine serum (FBS), 1% penicillin-streptomycin (10,000 U/mL-10,000 μg/ml) and 1% amphotericin B (250 μg/mL); all reagents from Gibco BRL, Grand Island, NY, USA. All cell lines were used between the third and fifth passages, which were confirmed and characterized as hPDL cells as previously described.4,5 Each experiment was performed in triplicate for the four independent cell lines.

2.2. Vibration and compressive force protocols

Human PDL cells (3 × 105 cells/well) were seeded into six-well plates, and were prepared for the experiments, as previously described.4 The cells were randomly allocated into six groups: control without mechanical stimulation (C), compressive force (CF), vibration at 30 Hz (V30), vibration at 60 Hz (V60), compressive force combined with 30 Hz vibration (V30CF) and compressive force combined with 60 Hz vibration (V60CF). The culture plates were subjected to mechanical vibration (magnitude, 0.3 g; 30 or 60 Hz; 20 min per cycle, every 24 h for 3 cycles) using a GJX-5 vibration calibrator (Beijing Sending Technology, Beijing, China) as described previously.4,5 Compressive force (2.0 g/cm2) was continuously applied for 2 days using a modified version of previously described protocol5; acrylic masses in glass cylinders were placed over 70–80% confluent cells. Combined compressive force and vibration were applied by mounting the compressed cells onto the GJX-5 platform. For the control cells, they were placed on the vibration platform for the same period of time but not subjected to vibration. All cells were collected immediately after the end of mechanical stimulation.

2.3. Analysis of IL-1β and TNF-α mRNA and protein expression

IL-1β and TNF-α mRNA were quantified using quantitative real-time polymerase chain reaction (qPCR) as described earlier,4 using the primer sequences listed in Table 1. The qPCR program was generated at 95 °C for 2 min, then 40 cycles of denaturation (95 °C, 5 s), annealing (60 °C, 20 s) and extension (72 °C, 20 s) were performed. The levels of expression were analyzed by the 2-ΔΔCT method, using GAPDH as an internal control.

Table 1.

Real-time PCR primers.

Gene Sequences Accession number Product size (bp)
IL-1β F: 5′-CACGCTCCGGGACTCACAGC-3′
R: 5′-CTGGCCGCCTTTGGTCCCTC-3′ 		NM_000576.3 400
TNF-α F: 5′-TTCTGCCTGCTGCACTTTGGA-3′
R: 5′-TTGATGGCAGAGAGGAGGTTG-3′ 		NM_000594.4 380
GAPDH F: 5′-GCACCGTCAAGGCTGAGAAC-3′
R: 5′-ATGGTGGTGAAGACGCCAGT-3′ 		NM_002046.5 142
Open in a new tab

F, Forward primer; R, Reverse primer.

IL-1β and TNF-α soluble proteins in the culture media were quantified using DuoSet® ELISA Development kits (R&D Systems Co., Minneapolis, MN, USA) against a standard curve and calibrated to total protein content.4

All mRNA and protein expression levels are presented as fold changes relative to control cells.

2.4. Statistical analysis

All values are the mean ± standard deviation for triplicate samples for the four independent cell lines. Differences between groups were compared using the Kruskal-Wallis test followed by the Mann-Whitney U test using SPSS software version 17.0 (SPSS, Chicago, IL, USA). P < .05 was considered significant.

3. Results

3.1. Effects of compressive force and mechanical vibration on IL-1β and TNF-α mRNA and protein in hPDL cells

Compressive force significantly upregulated IL-1β and TNF-α expression in hPDL cells compared to untreated control cells (P < .05; Fig. 1A–D). However, mechanical vibration at 30 or 60 Hz did not alter IL-1β or TNF-α expression compared to control cells (Fig. 1A–D).

Fig. 1.

Fig. 1

Open in a new tab

Relative expression of mRNA and protein in control (C) hPDL cells and cells exposed to compressive force 2.0 g/cm2 for 2 days (CF), vibration (0.3 g for 20 min per cycle, every 24 h for 3 cycles) at 30 or 60 Hz (V30 or V60) or a combination of compressive force and vibration at 30 Hz or 60 Hz (V30CF or V60CF). (A) IL-1β mRNA, (B) IL-1β protein (absolute values for control cells ranged from 35.33 ± 1.04 to 107.82 ± 7.91 pg/mg), (C) TNF-α mRNA and (D) TNF-α protein (absolute values for control cells ranged from 0.87 ± 0.46 to 1.44 ± 0.05 pg/mg). Results are presented as mean ± SD of triplicate experiments for four hPDL cell lines prepared from independent donors (n = 4). * indicates significant differences between group C and the intervention groups, + indicates significant differences between the intervention groups, (P < .05, Mann-Whitney U test).

The combination of both frequencies of vibration with compressive force (V30CF and V60CF) significantly increased IL-1β and TNF-α expression relative to control cells (P < .05; Fig. 1A–D). In addition, IL-1β mRNA and TNF-α mRNA and protein were significantly upregulated in V30CF but not V60CF group, compared to CF group (P < .05; Fig. 1A, C and D). However, IL-1β protein levels between V30CF and CF group did not reach statistical significance (Fig. 1B).

4. Discussion

We previously found that orthodontic force combined with vibration applied using an electric toothbrush (125 Hz) significantly increased IL-1β in GCF as well as the tooth movement rate.1 However, the clear cut mechanisms of how cells respond to vibratory stimulation have not been explained since the results are the combined responses of several cell types. Our previous study found vibration has no effect on IL-1β, IL-6 and RANKL expression in osteoblastic cells of human alveolar bone even if in combination with compressive force.8 We propose that the elevation of IL-1β in patients who received vibration accelerated tooth movement is the responsibility of PDL cells. This present study examined the effects of vibratory stimulation on hPDL cells in vitro which can define the response mechanisms of PDL cells to this mechanical stimulation.

Previously, our group found vibratory stimulation significantly increased COX-2, PGE2, IL-6, IL-8 and RANKL in hPDL cells in vitro.4, 5, 6, 7 In addition, different vibration frequencies (30, 60 and 90 Hz) had no significant different effects on PGE2 and RANKL expression.4 While, Judex et al.20 found different cellular activities and gene expressions in the cells response to different vibration frequencies (30 and 120 Hz).

In the present study, we applied vibration at different frequencies combined with compressive force to hPDL cells, simulation of different vibration frequencies activated the cells at the compression side of PDL to stimulate tooth movement in vivo.

According to Kanzaki et al.,21 RANKL mRNA was induced in a force- and time-dependent manner by compressive force in hPDL cells up to 48 h, with maximal response observed at 2 g/cm2. To make sure that this force protocol is not harmful to the cells, we used this compressive force protocol to combine with vibration in our pilot study. We found that cell morphology was unaffected under this condition. This corresponds with the study of Kanzaki et al.,21 which reported that hPDL cells can withstand compressive forces up to 3 g/cm2, 48 h without any damage to the cells. So, we combined this compressive force protocol (2 g/cm2, 48 h) with different frequencies of mechanical vibration to examine whether vibration synergistically enhances the ability of compressive force to induce IL-1β and TNF-α in hPDL cells.

This study found that 48 h exposure to compressive force (2 g/cm2) significantly upregulated IL-1β and TNF-α mRNA and protein in hPDL cells, similarly to previous reports.15,16 However, neither 30 nor 60 Hz vibrations alone significantly affected either IL-1β and TNF-α expression (Fig. 2A). These results suggest that these vibration protocols may be insufficient to activate or have no direct effect on IL-1β and TNF-α expression. On the other hand, application of combined 30 Hz vibration and compressive force synergistically enhanced IL-1β mRNA and TNF-α mRNA and protein (Fig. 2A). Vibration may increase the distortion of compressed PDL cells which can increase the activation of membrane-cytoskeleton phenomenon that regulates expression of inflammatory cytokine response to mechanical stimulation.22 In addition, vibration may enhance the effect of compressive force by reactivating the force, in the same way that intermittent compressive force maintains constant levels of cytokine expression.23 Moreover, the combination of the force may activate crosstalk between different pathways that regulate multiple cytokines and lead to synergistic effects. Further studies are required to investigate these effects. Interestingly, 30 Hz vibration combined with compressive force significantly increased IL-1β and TNF-α expression compared to compressive force alone, but 60 Hz vibration did not have this synergistic effect (Fig. 2A). This indicates the synergistic effects of combined vibration and compressive force on IL-1β and TNF-α are frequency dependent. According to study of Judex et al.,20 vibration with lower frequency has larger displacement of force resulting that it causes more distortion of the cell, which can activate the mechanotransduction pathways in the cell to express inflammatory cytokines, than higher frequency. This could be the reason why 30 Hz of vibration when combined with compressive force has more expression of IL-1β and TNF-α than 60 Hz. The present study validates that 30 Hz vibrations in combination with compressive force enhances the expression of IL-1β and TNF-α in hPDL cells, at least within the range of vibration frequencies tested.

Fig. 2.

Fig. 2

Open in a new tab

Diagram presents (A) effects of vibration at 30 or 60 Hz, compressive force and vibration at different frequencies combined with compressive force on human PDL cells, (B) the elevation of IL-1β in patients received vibration accelerated tooth movement may derive from, at least in part, the direct responses from PDL cells.

Even though the protein levels exhibited similar trends as the changes in mRNA expression, vibration at 30 Hz in combination with compressive force did not significantly upregulate IL-1β protein expression compared to compressive force alone. The large inter-individual variation in the protein levels of this group observed in this study may explain the non-significant between group differences. The health status of donors such as DMFT index and periodontal status may be the confounding factors affecting our results. Moreover, it is possible that IL-1β bioactivity may be inhibited by naturally occurring antagonists such as the IL-1 receptor antagonist, or anti-inflammatory cytokines that may be induced by a feedback mechanism.24,25 Thus, further studies using a large number of samples with more comprehensive study design to eliminate other confounders and/or the studies that investigate the effects of other factors are required to confirm this effect.

This in vitro study provides evidence that 30 Hz vibration synergistically enhanced compressive force-induced upregulation of IL-1β mRNA and TNF-α mRNA and protein in hPDL cells. This may imply that the elevation of IL-1β in patients received vibration accelerated tooth movement in our clinical study1 may derive from, at least in part, the direct responses from PDL cells (Fig. 2B). However, direct comparison between these studies are difficult because the use of different methods and vibration protocols. This study supports the use of vibration to accelerate orthodontic tooth movement and emphasizes that vibration frequency is the important factor determining the results. The data from our present and previous studies4, 5, 6, 7 suggest that 30 Hz vibration frequency is proper for combination with compressive force to stimulate inflammatory cytokines in vitro, which may be the proper frequency using for further clinical trials. However, there are some controversial results in clinical study due to highly complex of the actual in vivo responses. Further studies including in vitro and in vivo using animal and human, with the larger sample size are necessary to precisely explain how vibratory stimulation affects orthodontic tooth movement.

5. Conclusion

In this study, vibration alone either at 30 or 60 Hz had no effects on IL-1β and TNF-α expression in hPDL cells. On the other hand, when combined with compressive force, vibration at 30 Hz had the synergistic effects with compressive force on the upregulation of IL-1β mRNA and TNF-α mRNA and protein, while 60 Hz vibration did not have this synergistic effect.

Funding

This present study was supported by the Graduate School for Scholarship Awards for for Thai Ph.D. Students under Thailand’s Education Hub for Southern Region of Asean Countries.

Declaration of competing interest

The authors declare no conflicts of interest.

Acknowledgements

The authors wish to thank the Oral Neuroscience and Molecular Biology of Dental Pulp and Bone Cell Research Unit of the Faculty of Dentistry, Prince of Songkla University for the use of their facilities. The constructive comments provided by Prof. Dr. Prasit Pavasant are highly appreciated.

References

  • 1.Leethanakul C., Suamphan S., Jitpukdeebodintra S., Thongudomporn U., Charoemratrote C. Vibratory stimulation increases interleukin-1 beta secretion during orthodontic tooth movement. Angle Orthod. 2016;86:74–80. doi: 10.2319/111914-830.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Siriphan N., Leethanakul C., Thongudomporn U. Effects of two frequencies of vibration on the maxillary canine distalization rate and RANKL and OPG secretion: a randomized controlled trial. Orthod Craniofac Res. 2019;22:131–138. doi: 10.1111/ocr.12301. [DOI] [PubMed] [Google Scholar]
  • 3.Alikhani M., Alansari S., Hamidaddin M.A. Vibration paradox in orthodontics: anabolic and catabolic effects. PloS One. 2018;13 doi: 10.1371/journal.pone.0196540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Benjakul S., Jitpukdeebodintra S., Leethanakul C. Effects of low magnitude high frequency mechanical vibration combined with compressive force on human periodontal ligament cells in vitro. Eur J Orthod. 2018;40:356–363. doi: 10.1093/ejo/cjx062. [DOI] [PubMed] [Google Scholar]
  • 5.Phusuntornsakul P., Jitpukdeebodintra S., Pavasant P., Leethanakul C. Vibration enhances PGE2, IL-6, and IL-8 expression in compressed hPDL cells via cyclooxygenase pathway. J Periodontol. 2018;89:1131–1141. doi: 10.1002/JPER.17-0653. [DOI] [PubMed] [Google Scholar]
  • 6.Benjakul S., Leethanakul C., Jitpukdeebodintra S. Low magnitude high frequency vibration induces RANKL via cyclooxygenase pathway in human periodontal ligament cells in vitro. J Oral Biol Craniofac Res. 2019;9:251–255. doi: 10.1016/j.jobcr.2019.06.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Phusuntornsakul P., Jitpukdeebodintra S., Pavasant P., Leethanakul C. Vibration activates the actin/NF-kB axis and upregulates IL-6 and IL-8 expression in human periodontal ligament cells. Cell Biol Int. 2020;44:661–670. doi: 10.1002/cbin.11267. [DOI] [PubMed] [Google Scholar]
  • 8.Chatmahamongkol C., Pravitharangul A., Suttapreyasri S., Leethanakul C. The effect of compressive force combined with mechanical vibration on human alveolar bone osteoblasts. J Oral Biol Craniofac Res. 2019;9:81–85. doi: 10.1016/j.jobcr.2018.10.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Van S.A., Vander S.J., Geris L. A mechanobiological model of orthodontic tooth movement. Biomech Model Mechanobiol. 2013;12:249–265. doi: 10.1007/s10237-012-0396-5. [DOI] [PubMed] [Google Scholar]
  • 10.Zainal A.S.H., Yamamoto Z., Zainol A.I.Z., Megat A.W.R., Zainal A.Z. Cellular and molecular changes in orthodontic tooth movement. ScientificWorldJournal. 2011;11:1788–1803. doi: 10.1100/2011/761768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.A Ildeu, Jr., Silvana R.A., Paulo E.A.S. Inflammation and tooth movement: the role of cytokines, chemokines, and growth factors. Semin Orthod. 2012;18:257–269. [Google Scholar]
  • 12.O'Brien C.A., Gubrij I., Lin S.C., Saylors R.L., Manolagas S.C. STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-kappaB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone. J Biol Chem. 1999;274:19301–19308. doi: 10.1074/jbc.274.27.19301. [DOI] [PubMed] [Google Scholar]
  • 13.Uematsu S., Mogi M., Deguchi T. Interleukin (IL)-1 beta, IL-6, tumor necrosis factor-alpha, epidermal growth factor, and beta 2-microglobulin levels are elevated in gingival crevicular fluid during human orthodontic tooth movement. J Dent Res. 1996;75 doi: 10.1177/00220345960750010801. 562-267. [DOI] [PubMed] [Google Scholar]
  • 14.Teixeira C.C., Khoo E., Tran J. Cytokine expression and accelerated tooth movement. J Dent Res. 2010;89:1135–1141. doi: 10.1177/0022034510373764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Nakao K., Goto T., Gunjigake K.K., Konoo T., Kobayashi S., Yamaguchi K. Intermittent force induces high RANKL expression in human periodontal ligament cells. J Dent Res. 2007;86:623–628. doi: 10.1177/154405910708600708. [DOI] [PubMed] [Google Scholar]
  • 16.Kook S.H., Jang Y.S., Lee J.C. Human periodontal ligament fibroblasts stimulate osteoclastogenesis in response to compression force through TNF-alpha-mediated activation of CD4+ T cells. J Cell Biochem. 2011;112:2891–2901. doi: 10.1002/jcb.23205. [DOI] [PubMed] [Google Scholar]
  • 17.Li M., Zhang C., Yang Y. Effects of mechanical forces on osteogenesis and osteoclastogenesis in human periodontal ligament fibroblasts: a systematic review of in vitro studies. Bone Joint Res. 2019;8:19–31. doi: 10.1302/2046-3758.81.BJR-2018-0060.R1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Judex S., Lei X., Han D., Rubin C. Low-magnitude mechanical signals that stimulate bone formation in the ovariectomized rat are dependent on the applied frequency but not on the strain magnitude. J Biomech. 2007;40:1333–1339. doi: 10.1016/j.jbiomech.2006.05.014. [DOI] [PubMed] [Google Scholar]
  • 19.Lau E., Al-Dujaili S., Guenther A., Liu D., Wang L., You L. Effect of low-magnitude, high-frequency vibration on osteocytes in the regulation of osteoclasts. Bone. 2010;46:1508–1515. doi: 10.1016/j.bone.2010.02.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Judex S., Pongkitwitoon S. Differential efficacy of 2 vibrating orthodontic devices to alter the cellular response in osteoblasts, fibroblasts, and osteoclasts. Dose Response. 2018;16:1–8. doi: 10.1177/1559325818792112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Kanzaki H., Chiba M., Shimizu Y., Mitani H. Periodontal ligament cells under mechanical stress induce osteoclastogenesis by receptor activator of nuclear factor kappaB ligand up-regulation via prostaglandin E2 synthesis. J Bone Miner Res. 2002;17:210–220. doi: 10.1359/jbmr.2002.17.2.210. [DOI] [PubMed] [Google Scholar]
  • 22.Sackin H. Mechanosensitive channels. Annu Rev Physiol. 1995;57:333–353. doi: 10.1146/annurev.ph.57.030195.002001. [DOI] [PubMed] [Google Scholar]
  • 23.Lee K.J., Park Y.C., Yu H.S., Choi S.H., Yoo Y.J. Effects of continuous and interrupted orthodontic force on interleukin-1beta and prostaglandin E2 production in gingival crevicular fluid. Am J Orthod Dentofacial Orthop. 2004;125:168–177. doi: 10.1016/j.ajodo.2003.03.006. [DOI] [PubMed] [Google Scholar]
  • 24.Moldawer L.L. Interleukin-1, TNF alpha and their naturally occurring antagonists in sepsis. Blood Purif. 1993;11:128–133. doi: 10.1159/000170106. [DOI] [PubMed] [Google Scholar]
  • 25.Dayer J.M. Evidence for the biological modulation of IL-1 activity: the role of IL-1Ra. Clin Exp Rheumatol. 2002;20:S14–S20. [PubMed] [Google Scholar]

Articles from Journal of Oral Biology and Craniofacial Research are provided here courtesy of Elsevier

RESOURCES