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MMPs, IL-1, and TNF are Regulated by IL-17 in Periodontitis
A. Beklen1,2,3,
M. Ainola2,
M. Hukkanen2,4,
C. Gürgan5,
T. Sorsa6 and
Y.T. Konttinen1,4,7,*
1 Department of Medicine/Invärtes medicin, Helsinki University Central Hospital, Helsinki, Finland;
2 Institute of Biomedicine/Anatomy, University of Helsinki, Finland;
3 Medico-social Centre, Dental Clinic, Bogazici University, Istanbul, Turkey;
4 ORTON Orthopaedic Hospital of the Invalid Foundation, Helsinki, Finland;
5 Department of Periodontology, Faculty of Dentistry, Ankara University, Turkey;
6 Institute of Dentistry, University of Helsinki, Dept. of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, Finland;
7 COXA Hospital for Joint Replacement, Tampere, Finland
Correspondence: * corresponding author, yrjo.konttinen{at}helsinki.fi, Biomedicum Helsinki, PO Box 700 (Haartmaninkatu 8), FI-00029 HUS-Finland
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ABSTRACT
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Periodontitis is characterized by periodontal tissue destruction. Since interleukin-17 (IL-17) has been reported to up-regulate IL-1β and tumor necrosis factor-alpha (TNF- ), it was hypothesized that it is increased in periodontitis and up-regulates these cytokines and tissue-destructive matrix metalloproteinases (MMP) in local migrant and resident cells. Immunocytochemistry disclosed elevated IL-1β, TNF-, and IL-17 levels in periodontitis. These cytokines induced proMMP-1 and especially MMP-3 in gingival fibroblasts, whereas MMP-8 and MMP-9 were not induced. IL-17 was less potent as a direct MMP inducer than IL-1β and TNF-, but it induced IL-1β and TNF- production from macrophages, and IL-6 and IL-8 from gingival fibroblasts. In accordance with these findings, immunocytochemistry disclosed that MMP-1 and MMP-3 were increased in periodontitis. Gingival fibroblasts may play an important role in tissue destruction in periodontitis via cytokine-inducible MMP-1 and MMP-3 production, in which IL-17 plays a role as a key regulatory cytokine.
Key Words: IL-1β • TNF- • IL-17 • MMP • periodontitis
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INTRODUCTION
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Matrix metalloproteinases (MMPs) are important mediators of connective tissue destruction in periodontitis, including MMP-1, -3, -8, and -9 (Birkedal-Hansen et al., 1993). Macrophages and lymphocytes are locally activated to produce pro-inflammatory interleukin-1 (IL-1β), tumor necrosis factor- (TNF-), and IL-17 (Yao et al., 1995; Jovanovic et al., 1998), which are associated with a persistent over-expression of many MMPs (Liacini et al., 2005). Since fibroblasts are the predominant cells in gingival connective tissue, they likely participate in gingival pathology (Bronson et al., 1989; Konttinen et al., 2000).
MMP-1 can initiate extracellular matrix destruction and cooperates with other MMPs in collagen degradation (Woessner, 1991). It accounts for most of the collagenase activity expressed by cultured gingival fibroblasts (Sakaki et al., 2004). Increased MMP-1 mRNA expression, together with that of MMP-3, has been demonstrated in periodontitis (Kubota et al., 1996). MMP-1 and MMP-3 effectively degrade numerous extracellular matrix substrates, including collagens and proteoglycans. MMP-3 has the capacity to activate pro-MMP-1, pro-MMP-8, and pro-MMP-9 in activation cascades (Sorsa et al., 1990; Suzuki et al., 1990; Ogata et al., 1992). Increased MMP-1 and MMP-3 levels have been reported in gingival fibroblasts after stimulation with IL-1β and TNF- (Domeij et al., 2002). Thus, MMP-1 and MMP-3 in periodontitis appear to be locally produced and released in gingival tissue by activated fibroblasts (Ingman et al., 1994).
Increased mRNA expression for MMP-8 (Tonetti et al., 1993) and MMP-9 (Mäkelä et al., 1994) has also been reported in inflamed human gingiva. MMP-8 and MMP-9 mainly derive from polymorphonuclear leukocytes (Birkedal-Hansen et al., 1993), but are also synthesized by fibroblasts in chronic inflammation (Unemori et al., 1991). MMP-8 is the main collagenase in inflamed gingival crevicular fluid (Sorsa et al., 1988), and its IL-1-mediated regulation may contribute to severe periodontitis (Abe et al., 2001). The overall expression of MMP-9 is also increased in periodontitis (Birkedal-Hansen et al., 1993).
IL-6 is important in T-cell activation and proliferation and acts synergistically with IL-1β (Ishimi et al., 1990), whereas IL-8 is the major chemoattractant for polymorphonuclear leukocytes (Baggiolini et al., 1994). IL-1β and TNF- are the major inducers of IL-6 and IL-8, and, in this respect, IL-17 shows a synergistic effect with IL-1β and TNF- (Katz et al., 2001). IL-17 is a pro-inflammatory cytokine produced mainly by activated T-cells (Yao et al., 1995). IL-17 induces production of IL-6 and IL-8 in rheumatoid synovial fibroblasts (Hwang et al., 2004) and IL-6 in gingival fibroblasts (Takahashi et al., 2005). In addition, IL-17 enhances the effects of IL-β and TNF- on the synthesis of IL-6 and IL-8 in skin and synovial fibroblasts (Chabaud et al., 1998; Katz et al., 2001). We hypothesized that IL-17 plays an important role in the induction of some of the key pro-inflammatory cytokines produced and released by gingival fibroblast and peripheral blood-derived monocytes/macrophages. Since these cytokines are associated with periodontal tissue destruction, the increased levels of tissue-destructive proteinases (MMP-1, -3, -8, and -9) in periodontitis may result from activation of gingival fibroblasts by the pro-inflammatory IL-1β, TNF-, and IL-17.
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MATERIALS & METHODS
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Individuals and Gingival Tissue Samples
Gingival tissue samples were collected from ten adults with periodontitis (age range, 31–45 yrs) during routine periodontal flap surgery after the initial phase of periodontal therapy, consisting of scaling and root planing. Ten healthy control specimens were obtained from the extraction operations performed for retained wisdom teeth (age range, 20–37 yrs). None of the study participants had used antibiotics within the preceding 6 mos, smoked, or had used calcium channel-blockers, cyclosporine A, phenytoin, or any other drugs associated with gingival hyperplasia, which could have affected the gingival tissue MMPs. The periodontal status was assessed by plaque and gingival bleeding indices and probing depth (Ainamo and Bay, 1975). The ethics committee approved the plan, and informed consent was obtained. Samples were immediately fixed in phosphate-buffered 4% formol-saline solution prior to being processed into paraffin blocks.
Cell Cultures
Human gingival fibroblasts isolated by an explant culture technique were cultured in RPMI-1640 containing 10% fetal calf serum and antibiotics. Confluent fibroblasts were stimulated for 48 hrs with 10 ng/mL IL-1β, TNF-, or IL-17 (R&D Systems Inc., Minneapolis, MN, USA). Human monocytes from healthy persons were isolated from buffy coats by means of Ficoll-Paque gradient (Pharmacia Biotech, Uppsala, Sweden). Non-adherent cells were removed by repeat PBS washes, and adherent cells were stimulated for 48 hrs with 10 ng/mL IL-17 (R&D Systems). Culture supernatants were collected and stored at –70°C.
Enzyme-linked Immunosorbent Assay (ELISA)
The levels of proMMP-1 and total (pro- and active) MMP-3, MMP-8, and MMP-9, and IL-6 and IL-8 were analyzed from gingival fibroblast cultures, and IL-1β and TNF- were analyzed from monocyte/macrophage cultures. ELISA was performed with commercial sandwich ELISA kits (Quantikine, R&D Systems). The minimum detection limits were: proMMP-1, 0.095 ng/mL; MMP-3, 0.009 ng/mL; MMP-8, 0.02 ng/mL; MMP-9, 0.156 ng/mL; IL-1β, 3.9 pg/mL; IL-6, 3.12 pg/mL; IL-8, 31.2 pg/mL; and TNF-, 15.6 pg/mL.
Immunocytochemistry
The avidin-biotin-peroxidase complex method (Vectastain Elite ABC kit, Vector Laboratories, Burlingame, CA, USA) was used for immunocytochemical localization of IL-1β, TNF-, and pro-and active MMP-1 and MMP-3. Deparaffinized tissue sections were incubated with 6.5 µg/mL rabbit anti-human IL-1β IgG (Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA), 0.5 µg/mL rabbit anti-human TNF- IgG (Monosan, Uden, the Netherlands), 1 µg/mL mouse anti-human MMP-1 IgG (Chemicon International Inc., Temecula, CA, USA), or 11 µg/mL goat anti-human MMP-3 IgG (Santa Cruz). Immunolocalization of IL-17 was performed with DAKO TechMate Horizon automate (DAKO, Glostrup, Denmark) with 2 µg/mL goat anti-human IL-17 IgG (R&D Systems). Randomly selected images were captured with light microscopy at 20x objective magnification. The numbers of immunoreactive cells were counted in three randomly selected fields, with the use of semi-automated AnalySIS image analysis software (Soft Imaging Systems, AnalySIS, Munster, Germany).
Statistical Analysis
Statistical significances were calculated by the Student’s t test and analysis of one-way variance (ANOVA) with Bonferroni’s post-tests for multiple comparisons.
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RESULTS
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Expression of Cytokines in Gingival Tissues
The overall intensity of IL-1β, TNF-, and IL-17 immuno-reactivity was stronger in periodontitis than in the controls. An increase of approximately five-fold was noticed for IL-1β (1726 ± 81 vs. 344 ± 20) and four-fold for TNF- (1594 ± 147 vs. 411 ± 17) in periodontitis (p < 0.001). IL-1β and TNF- were localized predominantly in macrophages, fibroblasts, and epithelial and endothelial cells (Figs. 1A, 1B, 1D, 1E ). The number of IL-17 immunoreactive cells was six-fold higher (162 ± 21 vs. 26 ± 2) in periodontitis (p < 0.001), although their total number was much lower compared with those of IL-1β- and TNF--positive cells (Figs. 1C, 1F). IgG staining controls were negative.
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Figure 1. Immunolocalization of cytokines in gingival tissue. In healthy control samples, IL-1β (A), TNF- (B), and IL-17 (C) immunoreactive cells were less frequent (***p < 0.001) compared with cells in persons with periodontitis (D,E,F). IL-1β, TNF-, and IL-17 immunopositive cells in persons with periodontitis vs. healthy control individuals were 1726 ± 81 vs. 344 ± 20, 1594 ± 147 vs. 411 ± 17, and 162 ± 21 vs. 26 ± 2, respectively. The inserted figures are magnified 3x from original arrowed area. Scale bar = 100 µm. The histograms demonstrate the number of IL-1β-, TNF--, and IL-17-positive cells in controls and periodontitis.
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Induction by Cytokines of proMMP-1 and MMP-3 in Gingival Fibroblasts
Stimulation of gingival fibroblast cultures for 48 hrs with 10 ng/mL IL-1β or TNF- increased proMMP-1 (p < 0.01 for both) and MMP-3 (p < 0.001 for both). IL-17 had somewhat less pronounced direct stimulatory effects on proMMP-1 and MMP-3 concentrations (p < 0.05; Fig. 2). Cytokines did not induce MMP-8 or MMP-9 to a detectable level.
Expression of MMPs in Gingival Tissues
Since MMP-1 and -3 were induced by IL-1β, TNF-, and also IL-17, we next explored whether periodontitis tissue contained these MMPs. Cells immunoreactive for pro- and active MMP-1 and MMP-3 were higher in periodontitis than in controls (Fig. 3). MMP-1 and -3 were predominantly localized to stromal macrophages and fibroblast-like cells. MMP-1 immunoreactive cells were three-fold (1426 ± 96 vs. 497 ± 36) and MMP-3 four-fold (1103 ± 95 vs. 274 ± 14) higher (p < 0.001 for both) in periodontitis compared with controls.
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Figure 3. Immunolocalization of pro- and active MMP-1 (A,C) and MMP-3 (B,D) in gingival tissue. The numbers of MMP-1- and MMP-3-immunoreactive cells were increased in persons with periodontitis. The number of MMP-1-immunoreactive cells was 1426 ± 96 vs. 497 ± 36 (***p < 0.001) and MMP-3-immunoreactive cells 1103 ± 95 vs. 274 ± 14 (***p < 0.001) cells/mm2 in persons with periodontitis compared with healthy controls, respectively. Scale bar = 100 µm. The histograms demonstrate the numbers of MMP-1- and MMP-3-positive cells in control individuals and persons with periodontitis.
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IL-17-induced Synthesis of IL-6 and IL-8 in Gingival Fibroblasts
Stimulation of confluent gingival fibroblast cultures for 48 hrs with 10 ng/mL IL-17 increased nearly four-fold both IL-6 (p < 0.05) and IL-8 (p < 0.05) synthesis and release (Fig. 4A).
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Figure 4. Effect of IL-17 (10 ng/mL for 48 hrs) on induction of (A) IL-6 and IL-8 synthesis and release by gingival fibroblasts, and (B) IL-1β and TNF- synthesis and release by adherent human monocyte/ macrophages in vitro. The results are from triplicate measurements, n = 5, for both non-stimulated (black bars) and stimulated cultures (white bars). Means ± SEM are shown. *p < 0.05; analysis by t tests.
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IL-17-induced Synthesis of IL-1β and TNF- in Monocyte/Macrophages
Non-stimulated monocytes/macrophages did not release IL-1β or TNF-, but IL-17 induced them to release both IL-1β (0.59 ± 0.03 ng/mL) and TNF- (1.19 ± 0.24 ng/mL) (p < 0.05 for both) (Fig. 4B ).
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DISCUSSION
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Many previous studies have addressed the MMP-mediated mechanisms of periodontal tissue destruction (Kinane, 1992). In this study, it was shown that IL-1β, TNF-, and IL-17 are produced by healthy gingival tissue at low levels, but are highly elevated in periodontitis. Human gingival fibroblasts responded to IL-1β, TNF-, and IL-17 by production of proMMP-1 and MMP-3, whereas the responses of MMP-8 and MMP-9 were below the detection limit.
IL-1β and TNF- are involved in the initiation and progression of chronic inflammation (Birkedal-Hansen et al., 1993). They stimulate synthesis and release of MMP-1, MMP-3 (Domeij et al., 2002), MMP-8 (Hanemaaijer et al., 1997), and MMP-9 (Nee et al., 2004). Also, IL-17 can regulate some MMPs (Stamp et al., 2004). IL-17 appears to function in conjunction with IL-1β and TNF- to exacerbate inflammation (Ruddy et al., 2004). Takahashi and coworkers have speculated that the mechanism underlying T-cell infiltration in periodontitis may be, at least in part, via production of IL-17, which amplifies the severity of inflammation by acting on gingival fibroblasts to produce other inflammatory mediators, such as IL-6 (Takahashi et al., 2005). Fibroblasts are the predominant stromal cells of gingiva that play a prominent role in terms of production of MMPs (Birkedal-Hansen et al., 1993). Our present findings confirm and extend those of previous studies (Ingman et al., 1994), providing evidence of a significant increase in the number of cells immunoreactive for zymogen and active forms of MMP-1 and MMP-3 in periodontitis. Our results are in agreement with those of Domeij and co-workers, showing that gingival fibroblasts are capable of producing MMP-1 and MMP-3 as a result of IL-1β and TNF- stimulation (Domeij et al., 2002). In addition, we also provide evidence that IL-17 significantly increases proMMP-1 and total MMP-3 concentration within gingival fibroblasts. According to the current analyses, IL-1β and TNF- were more potent inducers of proMMP-1 and total MMP-3 compared with IL-17. It is of interest that, in periodontitis, the numbers of IL-17 immunoreactive cells were clearly increased, but to a lesser degree compared with IL-1β and TNF-.
Previous studies have shown that IL-17 may synergistically promote some of the functions of IL-1β and TNF-, such as osteoclastogenesis and bone resorption (Kotake et al., 1999). The present results indicate that IL-17 has fewer direct effects on MMP production than do IL-1β and TNF-, which seem to play the roles of "effector" cytokines. However, IL-17 was shown to stimulate the secretion of IL-6 and IL-8 by gingival fibroblasts and IL-1β and TNF- by monocyte/macrophages. Thus, it can be speculated that the effect of IL-17 on MMP-1 and MMP-3 synthesis and activity may function as a two-stage process. The first stage consists of direct stimulation of gingival fibroblasts to release IL-6 and IL-8 (Katz et al., 2001; Hwang et al., 2004; Takahashi et al., 2005). IL-6 stimulates local production of IL-1β and TNF- (Ishimi et al., 1990), whereas IL-8 may function as a local chemoattractant for polymorphonuclear leukocytes (Baggiolini et al., 1994). Second, macrophages release IL-1β and TNF- as a result of IL-17 stimulation (Jovanovic et al., 1998); these cytokines were shown effectively to induce the release of proMMP-1 and MMP-3 from gingival fibroblasts (Birkedal-Hansen et al., 1993). In agreement with these results, it seems that IL-1β and TNF- have a potent effect on the production of MMP-1 and MMP-3, whereas IL-17 seems to exert less potent direct regulatory effect on MMP production, but may function also via induction of IL-1β and TNF-.
Despite its relatively broad substrate specificity, MMP-3 cannot degrade the major interstitial collagens (Birkedal-Hansen et al., 1993). Therefore, the cooperative action of MMP-1 and MMP-3 may augment their joint proteolytic potential. Overproduction of MMP-1 and MMP-3 in gingival tissue may facilitate the destruction of extracellular matrix as fibroblasts effectively synthesize and release proMMP-1 and total MMP-3 as a response to stimulation with IL-1β, TNF-, and IL-17. However, this conclusion cannot be substantiated, since the antibody used in the present study to demonstrate gingival tissue MMP-1 recognizes only proMMP-1. It remains uncertain if indeed MMP-3 had been able to activate the proMMP-1 to its active counterpart.
MMP-8 and MMP-9 are released from polymorphonuclear leukocytes upon selective degranulation triggered by potent periodontopathogenic bacteria and their virulence factors (Ding et al., 1996, 1997). Some MMP-8 mRNA expression can be occasionally detected in gingival fibroblasts in periodontitis (Hanemaaijer et al., 1997). MMP-9 synthesis has been shown to occur in fibroblast-like cells from other sources as a response to stimulation with IL-1β and TNF- (Unemori et al., 1991). In our recent experiments, we have been particularly interested in local activation of MMP-3, MMP-8, and MMP-9 in gingival crevicular fluid (Beklen et al., 2006). For these reasons, we analyzed total MMP-8 and total MMP-9 production by gingival fibroblasts in parallel with proMMP-1 and total MMP-3. However, our results showed no detectable MMP-8 or MMP-9, regardless of stimulation with relatively high concentrations (10 ng/mL) of cytokines. The strong and direct correlation between MMP-8 and MMP-9 in gingival crevicular fluid from persons with periodontitis (Ding et al., 1996, 1997), with the results of the present study, suggests that MMP-8 and MMP-9 are derived mainly from polymorphonuclear leukocytes that migrate to gingival crevicular fluid (Beklen et al., 2006).
We conclude that IL-1β, TNF-, and IL-17 can induce the production of proMMP-1 and total MMP-3, but not total MMP-8 and total MMP-9, in gingival fibroblasts. IL-1β and TNF- were shown to have potent and possibly direct effects on MMP-1 and MMP-3 synthesis. However, it seems likely that these pro-inflammatory cytokines have synergistic effects on the production of MMP-1 and MMP-3, due to their involvement in local cytokine cascades, which are in part driven by IL-17.
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ACKNOWLEDGMENTS
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This study was supported by the Finnish Dental Society Apollonia, Helsinki University Central Hospital evo-grant, the Center of Excellence Program of the Academy of Finland, the National PhD Graduate School BGS of the Finnish Ministry of Education, and CIMO (Center for International Mobility). The authors thank Oguz Tanzer, PhD, for superb technical support and computer skills.
Received for publication March 24, 2006.
Revision received November 20, 2006.
Accepted for publication November 24, 2006.
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Journal of Dental Research, Vol. 86, No. 4,
347-351 (2007)
DOI: 10.1177/154405910708600409
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ABSTRACT
INTRODUCTION