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J Dent Res 84(12):1178-1182, 2005
© 2005 International and American Associations for Dental Research

RESEARCH REPORT
Biological

Role of TNF-{alpha} and Its Receptors in Pericoronitis

A. Beklen1,2,3, M. Laine1,2, I. Ventä4, T. Hyrkäs4, and Y.T. Konttinen1,5,6,*

1 Department of Medicine/Invärtes medicin, Helsinki University Hospital, Helsinki, Finland;
2 Institute of Biomedicine/Anatomy, University of Helsinki, Helsinki, Finland;
3 Medico-social Centre, Dental Clinic, Bogazici University, Istanbul, Turkey;
4 Finnish Student Health Service, Helsinki, Finland;
5 ORTON Orthopaedic Hospital of the Invalid Foundation, Helsinki, Finland; and
6 COXA Hospital for Joint Replacement, Tampere, Finland

* corresponding author, yrjo.konttinen{at}helsinki.fi, Biomedicum Helsinki, PO Box 700 (Haartmaninkatu 8), FIN-00029 HUS, Finland


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The classic stimulus for cellular cytokine production is bacterial lipopolysaccharide (endotoxin). It was therefore hypothesized that tumor necrosis factor-{alpha} (TNF-{alpha}) may be responsible for pericoronitis. TNF-{alpha} and its receptors were detected by immunohistochemical staining in third molar pericoronitis in ten patients and ten healthy control samples. The percentage of TNF-{alpha} positive cells was high in pericoronitis (p = 0.0317). TNF receptors TNF-R1 and TNF-R2 were found in macrophage- and fibroblast-like cells, vascular endothelial cells in post-capillary venules, and basal epithelial cells in pericoronitis, but were only weakly expressed in controls. Increased expression of interleukin-1ß and vascular cell adhesion molecule-1 was found as a biological indicator of TNF-{alpha} ligand-receptor interaction. Explanted tissues acquired destructive potential upon TNF-{alpha} stimulation, whereas TNF-{alpha} blockers controlled it in inflamed tissues. These findings suggest that, in pericoronitis, inflammatory and resident cells produce and respond to potent pro-inflammatory cytokine TNF-{alpha}, with pathogenic and potential therapeutic relevance.

KEY WORDS: pericoronitis • tumor necrosis factor-alpha • TNF-R1 • TNF-R2


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS & METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Pericoronitis is an inflammation of the soft and hard tissues surrounding the crown of an erupting or impacted tooth. It is characterized by Gram-negative anaerobic bacterial growth (Orbak and Dayi, 2003). Bacterial products stimulate host cells to secrete pro-inflammatory cytokines, which are necessary for host defense, but which may also lead to pain and periodontal tissue destruction (Gemmell et al., 1997; Palladino et al., 2003). Pericoronitis may occur at any age and in any tooth, but third molars most commonly present with this problem (Orbak and Dayi, 2003). Symptoms from pericoronitis vary from localized to general. Tooth extraction is the cornerstone of treatment and prophylaxis. In contrast, these teeth are of potential future value as important anchorage points for dentures (Peltroche-Llacsahuanga et al., 2000). Local host reactions around erupting teeth and in inflamed pericoronitis tissues may reflect mechanisms responsible for normal tooth eruption, inflammation, and tissue destruction in pericoronitis.

As part of our attempts to improve our understanding of the processes associated with retained third molars and pericoronitis, we analyzed the activation state of local cells by identifying an inducible pro-inflammatory cytokine, tumor necrosis factor-{alpha} (TNF-{alpha}), which can be used as a marker for cellular and tissue activation. TNF-{alpha} responsiveness of pericoronitis tissues was assessed by analysis of its two receptors, TNF-R1 and TNF-R2, on local resident and inflammatory cells. TNF-{alpha}, together with interleukin-1ß, plays an important role in tissue destruction (Hanemaaijer et al., 1997; Palladino et al., 2003). Finally, interleukin-1ß (IL-1ß) and vascular cell adhesion molecule-1 (VCAM-1) were analyzed as potential biological indicators of TNF-{alpha}-receptor interaction.

Since the classic stimulus for cellular cytokine production is bacterial lipopolysaccharide (endotoxin), it was hypothesized that TNF-{alpha} may be locally increased in pericoronitis tissues, and that these tissues also contain potential target cells responsive to its pro-inflammatory effects.


   MATERIALS & METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This study was approved by the ethical committee of the Finnish Student Health Service, Helsinki, Finland, and informed consent was obtained from all patients.

Patients and Samples
Ten control subjects, median age 23 yrs (range, 19–26 yrs), were asymptomatic students at the University of Helsinki, Finland. They underwent a thorough dental examination at the Finnish Student Health Service. According to orthopantomography, they had retained or partially erupted third molars, but they did not have generalized or local symptoms, such as pain or tenderness. Clinical examination did not demonstrate any signs of ongoing inflammation, such as swelling or erythema. They were offered a prophylactic third molar extraction. Ten patients were also students, median age 24 yrs (range, 20–30 yrs). Orthopantomography disclosed partially erupted third molars, but, despite lack of subjective symptoms, there was local swelling and redness. Asymptomatic, but clinically evident, pericoronitis was diagnosed. Third molar extraction was recommended and was done several days later. None of the students had used antibiotics within the preceding 6 mos. After an oral surgeon applied local anesthesia to the left and/or right mandibular third molar, teeth were extracted. Tissue samples were snap-frozen and stored at –70°C.

Collection of Tissue Samples and Explant Culture for MMP-9 Evaluation
Five clinically inflamed and 5 healthy gingival tissue samples were obtained during the surgical removal of the third molars. Tissue specimens were immediately placed in Eppendorf tubes and transported to the laboratory at +4°C.

Fresh healthy tissue samples were weighed and cut into small pieces (approximately 1 mm3 each); 6 or 7 explants per well were placed into 96-well plates. Tissues were incubated in RPMI-1640 medium containing 10% fetal calf serum and antibiotics at 37°C in 5% CO2, either without or with TNF-{alpha} (10 ng/mL, R&D Systems Inc., Minneapolis, MN, USA) for 48 hrs. Supernatants were harvested and frozen at –70°C until they were used for MMP-9 analysis by gelatin zymography.

Inflamed tissues were similarly prepared and treated without or with TNF-{alpha} blocker, namely, Infliximab (Centocor, Horsham, PA, USA), at 10 µg/mL for 48 hrs before supernatants were harvested and frozen at –70°C.

Immunohistochemistry
Cryostat sections (6 µm thick) were stained as described elsewhere (Tervahartiala et al., 2001; Mandelin et al., 2003). (See APPENDIX for details.)

Zymography
Gingival tissue supernatants were analyzed for gelatinolytic activities by zymography, with 7.5% SDS-polyacrylamide gels containing 1 mg/mL gelatin substrate (Ding et al., 1997). The bands on the gel were analyzed by Image J software (National Institutes of Health [NIH], Bethesda, MD, USA) as described elsewhere (VanSaun et al., 2003).

Evaluation and Statistical Analysis of Immunostaining
Three randomly selected areas of each slide were analyzed at 40x magnification (see APPENDIX).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Pericoronitis samples displayed histopathological features of chronic inflammation in the form of occasional perivascular and diffuse inflammatory cell infiltrates. The phenotype of the local migrant and resident cells has been previously described (Laine et al., 2003).

Tumor Necrosis Factor-{alpha}
TNF-{alpha} staining was found in all samples. It was most apparent in cells, whereas staining of peri- and extracellular matrix and basement membrane was very weak. The cellular staining pattern was cytoplasmic and diffuse, rather than granular or restricted to the cell membrane. In pericoronitis, positively stained cells were more frequent than in controls. In pericoronitis, TNF-{alpha} was found in fibroblast- and macrophage-like cells (occasionally organized into small inflammatory cell infiltrates), vascular endothelial cells, and basal and suprabasal epithelial cells (Fig. 1AGo, upper and lower inserts). Staining controls confirmed the specificity of staining (Fig. 1BGo). In healthy controls, TNF-{alpha} staining was weak (Fig. 2AGo), and most of the TNF-{alpha}-positive cells were stromal fibroblast-like cells or vascular endothelial cells. Very few TNF-{alpha}-positive macrophage-like cells were observed in interstitial stroma in healthy controls. Morphometric calculations disclosed a difference between pericoronitis and healthy controls in the percentage of TNF-{alpha}-positive cells: 62% (range, 45–72) vs. 34% (range, 10–51), p = 0.0317, respectively.



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  		Figure 1. Tumor necrosis factor-{alpha} (TNF-{alpha}) and its receptors in pericoronitis. (A) TNF-{alpha} is localized in basal and suprabasal cells, basement membrane, monocyte/macrophage-, fibroblast-like, and vascular endothelial cells. Upper and lower inserts: Twice-magnified images of TNF-{alpha}-positive cells in the lamina propria. (B) No staining was detected in the negative control. (C) TNF-R1 in serial tissue sections is localized in monocyte/macrophage- and fibroblast-like cells, and vascular endothelial and basal epithelial cells. Upper and lower inserts: Twice-magnified images of TNF-R1-positive cells in the lamina propria. (D) TNF-R2 in a serial section is localized in monocyte/macrophage-and fibroblast-like cells, and vascular endothelial and basal epithelial cells. Upper and lower inserts: Twice-magnified images of TNF-R2-positive cells in the lamina propria. Scale bar = 200 µm.

 


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  		Figure 2. TNF-{alpha} and its receptors in healthy control samples. (A) TNF-{alpha} is almost exclusively localized in fibroblast-like cells and vascular endothelial cells. (B) TNF-R1 in a serial section is localized in stromal fibroblast-like cells and vascular endothelial cells. (C,D) Larger magnifications from the same samples but from different areas, showing TNF-{alpha} and TNF-R1 staining, respectively. (E) In a serial section, weak TNF-R2 staining was occasionally found in a few stromal fibroblast- and macrophage-like, vascular endothelial, and basal epithelial cells. Scale bar = 200 µm.

 
Tumor Necrosis Factor-R1 Staining
TNF-R1-positive cells were found in all samples studied. TNF-R1 staining was cytoplasmic and not confined to the cell surface. In pericoronitis, TNF-R1 staining was observed in monocyte/macrophage- and fibroblast-like cells, vascular endothelial, and basal epithelial cells (Fig. 1CGo, upper and lower inserts). Vascular endothelial cell staining was observed particularly in post-capillary venules (Fig. 1CGo, lower insert). In contrast, in healthy controls, TNF-R1 staining was weak and found mainly in some vascular endothelial cells, stromal fibroblast- and macrophage-like cells, and basal epithelial cells (Figs. 2B, 2DGo).

Tumor Necrosis Factor-R2 Staining
TNF-R2-positive cells were found only in pericoronitis samples, whereas TNF-R2 staining was very weak or absent in healthy controls. In pericoronitis, TNF-R2 was found in fibroblast- and macrophage-like cells, vascular endothelial cells, and basal cells (Fig. 1DGo, upper and lower inserts). Vascular endothelial cell staining was observed in post-capillary venules (Fig. 1DGo, lower insert). TNF-R2 was not found in suprabasal epithelial cells. In healthy control samples, TNF-R2 was found in only a very few stromal fibroblast- and macrophage-like cells, vascular endothelial cells, and basal cells, which stained very weakly (Fig. 2EGo). Staining controls were completely negative and confirmed the specificity of TNR-R1 and -R2 staining (data not shown).

IL-1ß and VCAM-1 Staining
IL-1ß was found in all pericoronitis and control tissue samples (Figs. 3A, 3CGo, respectively). IL-1ß-positive cells were increased in pericoronitis: 60% (range, 55–72) vs. 25% (range, 23–40), p = 0.0079 (Mann-Whitney test). IL-1ß was found in macrophage- and fibroblast-like cells, vascular endothelial cells, and epithelial cells (Fig. 3AGo). In healthy samples, IL-1ß staining was weaker and located mostly in vascular endothelium; it was observed only rarely elsewhere (Fig. 3CGo).



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  		Figure 3. IL-1ß and VCAM-1 in pericoronitis (A,B, respectively) and healthy tissues (C,D, respectively). In pericoronitis (A), IL-1ß was found in fibroblast - and macrophage-like, vascular endothelial, and epithelial cells. (B) VCAM-1 was mainly localized in endothelial cells of the subepithelial blood vessels. In healthy controls (C), most of the IL-1ß-positive cells were vascular endothelial cells. Very few and weakly IL-1ß-positive subepithelial cells were observed in healthy controls. (D) VCAM-1 was rare. Scale bar = 200 µm; inserts were twice-magnified.

 
VCAM-1-positive cells were more frequent in diseased than in control samples, 22% (range, 18–25) vs. 2.4% (range, 2.3–3.2), p = 0.0079 (Figs. 3B, 3DGo, respectively). The majority of the endothelial cells were VCAM-1-positive, except in the most superficial layers (Fig. 3BGo, insert), whereas the other cell types were only rarely or weakly positive in pericoronitis. In healthy controls, expression was nearly absent, although occasional endothelial cells seemed to be weakly positive (Fig. 3DGo, insert).

Zymography
Gelatin zymography results indicated two- to five-fold higher proMMP-9 and active MMP-9 expression in stimulated healthy tissues against non-stimulated samples after exposure to 10 ng/mL TNF-{alpha} (Fig. 4AGo). In contrast, expression of both proMMP-9 and active MMP-9 in inflamed tissue samples was down-regulated two- to five-fold with TNF-{alpha}-blocker (Fig. 4BGo).



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  		Figure 4. Gelatinolytic activities of the cultured tissue supernatants were studied with zymography. (A) Representative results from non-stimulated (–) and TNF-{alpha}-stimulated (+) healthy tissue sample supernatants at 48 hrs. (B) Inflamed tissue without (–) and with (+) TNF-{alpha} blocker showed reverse findings at 48 hrs. Molecular-weight standards (kDa) are marked to the left (7.5% acrylamide separating gel containing 1 mg/mL gelatin).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS & METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Pericoronitis affects especially young adults and is caused by infection-provoked inflammation around partially erupted third molars (Blakey et al., 1996). Previous studies have shown that, in clinically inflamed pericoronitis samples, mononuclear inflammatory cells, such as macrophages and lymphocytes, migrate to connective tissue around partially erupted third molars (Laine et al., 2003). However, it is not known if such cells are innocent bystanders or active participants. Resting monocyte/macrophages either do not produce any TNF-{alpha} or produce it only at low concentrations (Ferrero et al., 2001; Szlosarek and Balkwill, 2003). Upon activation by bacterial endotoxins, they start to produce TNF-{alpha}. After intracellular synthesis of TNF-{alpha}, it is transported to the cell surface and solubilized by a TNF-{alpha} converting enzyme (TACE), thus becoming able to affect its target cells auto- and paracellularly. Since TNF-{alpha} is a marker of cellular activation, we conclude that the resident cells—including fibroblast-like stromal, vascular endothelial, and basal and suprabasal epithelial cells around partially erupted, inflamed third molar pericoronitis—participate actively in the local inflammatory processes. Apparently, local inflammatory cells also participate. This conclusion is based on the high number and intense staining of the TNF-{alpha}-positive producer cells in pericoronitis compared with healthy controls.

TNF-{alpha} can exert its effects only on cells that express receptors for TNF-{alpha} (Springer, 1995). The TNF receptor staining pattern was cytoplasmic, i.e., it was not restricted to the cell membrane, which would give a rim-like staining pattern. However, this probably means only that TNF receptors are so actively produced by the positively staining cells, that staining is observed in the cell cytoplasm. After intracellular synthesis, TNF receptors are transported to the surface of the cell, where they can act juxtacellularly. The cytoplasmic staining pattern does not exclude cell membrane staining, but it is not possible to see cell membrane staining apart from the strong cytoplasmic staining. This has also been shown by others, who have reported and shown cytoplasmic staining patterns of TNF receptors in synovial tissues (Deleuran et al., 1992).

Relatively extensive and intense TNF-R1 and TNF-R2 staining was found on post-capillary venules in pericoronitis, suggesting the local up-regulation of vascular TNF receptors. It has been shown that the TNF-{alpha} blockade, with neutralizing antibodies or soluble decoy receptors, diminishes inflammation in rheumatoid arthritis, Crohn’s disease, and experimental periodontitis (Oates et al., 2002). Matrix metalloproteinases are important mediators of pathologic tissue destruction and leukocyte recruitment in periodontal tissues (Birkedal-Hansen et al., 1993). Earlier, we showed that the numbers of TNF-{alpha}-containing producer and responder cells are increased in adult periodontitis compared with healthy controls (Tervahartiala et al., 2001). Results from our current study suggest that excessive numbers of TNF-{alpha}-containing producer cells, combined with high numbers of TNF-receptor-positive target cells, may participate in a cascade leading to MMP-9 production and activation. This was demonstrated when we added TNF-{alpha} into non-inflamed healthy tissues, which then started to produce high amounts of proMMP-9, which was also converted to the active MMP-9 enzyme species. In contrast, inflamed tissue samples, spontaneously, already had such a phenotype, apparently due to stimulation in vivo; however, the phenotype could be controlled by TNF blockers. Indeed, it has already been shown that inhibition of TNF is effective in the treatment of various diseases. TNF-{alpha} blockers neutralize the biological activity of TNF-{alpha} by binding with high affinity to soluble and transmembrane forms of TNF-{alpha}, and competitively inhibit binding of TNF-{alpha} with its receptors (Knight et al., 1993; Siegel et al., 1995). Because of these results, it has been concluded that binding of TNF-{alpha} to its receptor plays a role in inflammation.

Lipopolysaccharides stimulate cells to secrete TNF-{alpha}, which can induce other cytokine cascades (Ghezzi et al., 2000). The pocket around a partially erupted dental crown forms a suitable ecological niche for anaerobic Gram-negative rod-shaped bacteria rich in lipopolysaccharides (Beck et al., 1996; Aggarwal, 2003). It was therefore hypothesized that the number of TNF-{alpha}-containing cells is increased in pericoronitis, as a result of recruitment and/or local activation, which was also found. In pericoronitis, TNF-{alpha} was not confined to basal epithelial cells, but was also found in suprabasal epithelial cells. Perhaps lipopolysaccharides penetrate the epithelium from above. Juxtacrine, autocrine, paracrine, and endocrine responses to TNF-{alpha} are mediated through TNF-R1 and TNF-R2 (Klinger et al., 1998; Kacinski and Flick, 2001). Some of the relevant target cells, such as vascular endothelial cells, seemed to contain TNF-{alpha}, TNF-R1, and TNF-R2 on serial sections. Since we did not conduct double-staining experiments, we cannot definitely confirm this or assess eventual double-positivity at the single-cell level for fibroblast-and macrophage-like cells.

TNF-{alpha} stimulates IL-1ß expression (Vilcek and Lee, 1991) and, together, these molecules both induce and up-regulate VCAM-1 (Haraldsen et al., 1996; Lawson et al., 1999). We therefore analyzed IL-1ß and VCAM-1 in pericoronitis as a potential biological indicator of TNF-{alpha}-receptor interaction. It was found that IL-1ß- and VCAM-1-positive cells were more frequent and stained more intensely in pericoronitis than in controls. Apart from their important and independent potential role in pericoronitis (Stemerman, 2000), this also indirectly suggests that TNF-{alpha}-TNFR interactions occur in pericoronitis.

In summary, we conclude that TNF-{alpha} and its receptors may play an important and active role in pericoronitis. This observation sheds light on the pathogenesis of pericoronitis as well as tooth eruption. TNF-{alpha} can be modulated by TNF-blockers, which are used in the treatment of systemic inflammatory bowel and joint diseases (Maini et al., 1999; Weinblatt et al., 1999). Their systemic use has been hampered somewhat due to high cost and systemic adverse effects, such as infections, including activation of latent tuberculosis. State-of-the-art management of pericoronitis consists of third molar extraction and the use of antibiotics. Based on studies of disease pathogenesis and inflammation in general, the possibility of applying TNF-blockers locally or by injection via suitable carriers—such as collagen, alginate, or hyaluronan—offers interesting new possibilities for experimental studies of tooth migration, eruption, and pericoronitis.


   ACKNOWLEDGMENTS
 
This study was supported by Helsinki University Central Hospital evogrant, the Center of Excellence Program of the Finnish Academy, and the National PhD Graduate School BGS of the Finnish Ministry of Education.


   FOOTNOTES
 
A supplemental appendix to this article is published electronically only at http://www.dentalresearch.org.

Received August 18, 2004; Last revision August 4, 2005; Accepted August 4, 2005


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 DISCUSSION
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