Anti-inflammatory cytokines in gingival crevicular fluid in patients with periodontitis and rheumatoid arthritis: A preliminary report

www.elsevier.com/locate/issn/10434666 Cytokine 35 (2006) 180–185

Anti-inflammatory cytokines in gingival crevicular fluid in patients with periodontitis and rheumatoid arthritis: A preliminary report Fatma Yesßim Bozkurt a, Zuhal Yetkin Ay

a,*

, Ezel Berker b, Eser Tepe b, Selami Akkusß

c

a

c

Su¨leyman Demirel University, Faculty of Dentistry, Department of Periodontology, Isparta, Turkey b Hacettepe University, Faculty of Dentistry, Department of Periodontology, Ankara, Turkey Su¨leyman Demirel University, Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Isparta, Turkey Received 3 January 2006; accepted 26 July 2006

Abstract Cytokines which are produced by host cells play an important role in pathogenesis both rheumatoid arthritis (RA) and chronic periodontitis (CP). In this study, we aim to investigate the levels of Interleukin (IL)-4 and IL-10 in gingival crevicular fluid (GCF). Seventeen patients with CP, 17 patients with RA and 17 healthy controls (HC) were included. The RA group was divided into two groups according to gingival sulcus depths (RA-a: PD 6 3 mm, (n = 12), RA-b: PD > 3 mm, (n = 5)). For each patient, clinical parameters were recorded. The GCF samples were evaluated by enzyme-linked immunosorbent assay (ELISA) for IL-4 and IL-10 levels. IL-4 levels in the RA-a, RA-b and CP subjects were significantly lower compared to the HC subjects (p < 0.05). The mean level of IL-4 in RA-b group was significantly higher than that in CP group (p < 0.05). IL-10 mean level in the HC group was higher than those in the other groups (p < 0.05). In the RA-a group, higher IL-10 level was found compared to the CP patients (p < 0.05). Within the limitations of this preliminary report, it can be concluded that the initiation and progression of periodontal inflammation may be due to a lack or inappropriate response of the anti-inflammatory cytokines in both CP and RA. Ó 2006 Elsevier Ltd. All rights reserved. Keywords: Periodontal disease; Rheumatoid arthritis; GCF; IL-4; IL-10

1. Introduction The immune response underlying the pathogenesis of the chronic inflammatory diseases such as chronic periodontitis (CP)1 and rheumatoid arthritis (RA) has been studied for the past three decades [1–3]. The major tissue destruction in established periodontitis lesions results from the recruitment of host cells via activation of mononuclear phagocytes, including monocytes and macrophages, T and B cells and other cell types like RA lesions [3–6]. One of the *

Corresponding author. Fax: +246 2370607. E-mail address: [email protected] (Z. Yetkin Ay). 1 Abbreviations: CP, chronic periodontitis; RA, rheumatoid arthritis; HC, healthy controls; IL, interleukin; PD, probing depth; GI, gingival index; PI, plaque index; GBTI, gingival bleeding time index; CAL, clinical attachment level; GCF, gingival crevicular fluid; ELISA, enzyme linked immunosorbent assay; IFN-c, Interferon-c; TNF-b, Tumor Necrosis Factor-b; PGE2, Prostoglandin E2; TNF-a, tumor necrosis factor-a. 1043-4666/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2006.07.020

important effects of memory or native T cells and monocytes is the synthesis of cytokines, which modulate the inflammatory response [7–9]. T cell functions in humans can be analyzed by studying their cytokine profiles. Th1 clones produce Interleukin (IL)-2, interferon (IFN)-c and tumor necrosis factor (TNF)-b and Th2 clones produce IL-4, IL-5, IL-6, IL-10 and IL-13 [10]. IL-4 enhances the stimulation of Th2 cells and inhibits the functions of Th1 cells [11] and monocytes/macrophages [12]. It has been reported that the lack of IL-4 may cause the accumulation of macrophages, increased CD14 expression and the high production of inflammatory mediators such as prostoglandin E2 (PGE2), TNF-a and IL-1b in periodontal tissue [13]. IL-10 is also a potent inhibitor both Th1 cytokines (IL-2 and IFN-c) and monocyte/macrophage products [14–17]. It has been suggested that it has a regulatory effects in periodontal inflammation [18–20].

F.Y. Bozkurt et al. / Cytokine 35 (2006) 180–185

Recent studies have focused on the clarification of the relationship between RA and CP due to the similarity of their pathogenesis. Active tissue destruction, the cell infiltrations and inflammatory mediators (PGE2, TNF-a and IL-1b) are similar in both diseases [3,6,21–25]. It was suggested that the lack of anti-inflammatory cytokines such as IL-4 and IL-10 may contribute the initiation and progression of inflammation during chronic synovitis in RA joints [25–27]. Since Th1, Th2 and monocyte cytokines are also found in gingival tissues and GCF, even a minimal imbalance of between pro- and anti-inflammatory cytokine production may contribute to bone and collagen destruction in periodontal diseases [28]. Therefore, evaluating the levels of anti-inflammatory cytokines in GCF in both diseases may determine the protective aspects of these cytokines in CP and RA patients. This study aimed to evaluate the levels of anti-inflammatory cytokines (IL-4 and IL-10) in GCF and to determine the correlations between the clinical parameters and the levels of cytokines in CP and RA patients. 2. Materials and methods 2.1. Patient selection The study was conducted in patients who were referred to the Department of Periodontology for their periodontal treatment needs from January 2005 to September 2005. Fifty-one subjects who fit the inclusion criteria below were divided into three groups: (1) CP (n = 17, 6 females, 11 males; mean age: 43.88 ± 9.69); (2) RA (n = 17, 12 females, 5 males; mean age: 47.18 ± 11.34); and (3) HC (n = 17, periodontally healthy subjects, 8 females, 9 males; mean age: 36.29 ± 3.55). The protocol was clearly explained to all groups, informed consent was signed. 2.2. Inclusion and exclusion criteria In the CP and RA groups, all of the patients had chronic periodontitis. The diagnosis was made according to the clinical and radiographic criteria (more than 30 years old, loss of clinical attachment greater than 2 mm at two or three sites in more than 3 teeths in each quadrant, and radiographic evidence of bone loss). The HC group was consisted of the volunteers who were periodontally and systemically healthy. None of the subjects had taken medications such as antibiotics, anti-inflammatory drugs, or contraceptives for at least 3 months prior to the study, nor had any systemic diseases, except the RA group. None of the RA patients included in this study had xerostomia. All of the RA patients had been receiving drug therapy including prednisolone, 5 mg/day; indomethacin, 75 mg/day; and chloroquine, 250 mg/day. Patients in all groups had no previous history of periodontal therapy or professional treatment to prevent periodontitis in the last six months. None of the patients were smokers.

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2.3. Clinical parameters Clinical parameters were taken at full-mouth and sample-sites for each patient by skilled clinician. Probing depth (PD), gingival index (GI) [29], plaque index (PI) [30], gingival bleeding time index (GBTI) [31], and clinical attachment level (CAL) values were recorded. The measurements were made with a Williams probe. For PD and CAL measurements the probe was directed in line with the long axis of the tooth. CAL measurements were made from the cemento-enamel junction to the bottom of the sulcus. 2.4. GCF sampling The GCF samples were obtained from the maxillary anterior area in order to avoidance of salivary contamination and because of easy GCF collection. The patients were included to the study if they had at least 4 teeth and 4 non-adjacent sites for the GCF sampling in the maxillary anterior area. Local predisposing factors like the caries, unfitted restorations, disposition of the teeth in the dental arc, bruxism, mouth breathing, dry mouth, etc. were determined as exclusion criteria for the anterior sites. The sampling was performed after the PI score and before all of the clinical parameters, in order to avoid mechanical irritation and/or bleeding by the penetration of the probe. If present, supragingival plaque was removed from each tooth determined for sampling. Teeth were gently dried with an air spray and isolated with cotton rolls. A saliva ejector was used to avoid salivary contamination. Periopaper Gingival Fluid Collection Strips2 were held within the gingival sulci for 30 s in the maxillary anterior area in each patient. Strips contaminated by bleeding were discarded. Periotron 80003 was used to determine the amount of GCF. Each sample was stored at 80 °C until assayed. Patients with RA were divided into two groups in accordance with the probing depths in maxillary anterior area (between the upper second premolars): (1) RA-a (n = 12) (PD 6 3 mm). (2) RA-b (n = 5) (PD > 3 mm). In CP group, 102 samples from 68 teeth, in RA-a group 72 samples from 52 teeth, in RA-b group 30 samples from 25 teeth, and in HC group 102 samples from 102 teeth were obtained. 2.5. IL-4 and IL-10 analysis Each strip was eluted twice with 100 lL of Hank’s balanced salt solution containing 0.5% bovine serum albumin by centrifugation (3000g, 4 °C, and 15 min). For IL-4 and IL-10 assays, high-sensitive kits4 were used to detect the

2 3 4

Pro Flow Inc, USA. Oraflow Inc., Plainview, NY, USA. R&D Systems, Minneapolis, USA.

0.88 ± 0.39b,c 1.77 ± 0.66b,d 1.96 ± 0.62b 0.09 ± 0.17a,d,c 1.62 ± 0.38a 2.54 ± 0.46a,b 3.29 ± 0.55b,d,c 1.12 ± 0.70a,c

GI PD (mm) GI PD (mm)

CAL (mm) GBTI

3.3. Correlations

PI

The correlations between the cytokine concentrations and clinical parameters have presented in Table 2. Strong correlations between the cytokines were found in CP and RA-a groups (p < 0.01). PI has presented negative correlations with both of the cytokines in CP group (r = 0.516 with IL-4, r = 0.494 with IL-10; p < 0.05).

Cytokine values for all groups are presented as concentration (pg/lL) in Fig. 1. IL-4 levels were found significantly lower in the RA groups and CP compared to that of the HC group (p < 0.05). The lowest level of IL-4 was found in CP group. The GCF IL-10 level in HC was higher than RA-a, RA-b and CP groups, respectively. The statistically significant differences were found between the RA-a and CP, RA-a and HC, RA-b and HC, CP and HC groups (p < 0.05). RA-b and CP groups have not displayed a statistically significant difference (p > 0.05).

Table 1 Clinical parameter data (mean ± SD)

3.4. Cytokine concentrations

1.07 ± 0.42a,b 1.63 ± 0.55b 1.87 ± 0.251b 0.19 ± 0.51a,d,c

In sample sites, all the mean clinical parameter data in the HC group were lower than those in the other groups (p < 0.05). The mean PD and CAL values in RA-b were significantly higher than those in the RA-a group (p < 0.05). All indices except for GI in the CP group were significantly higher than RA-a group (p < 0.05).

2.04 ± 0.82a,b 4.02 ± 1.34b 4.98 ± 1.83b 1.14 ± 0.09a,d,c

Sample site Full mouth

3.2. Clinical parameter values (sample sites)

2.31 ± 4.02b 2.09 ± 0.61b 2.35 ± 0.66b 0.29 ± 0.47a,d,c

The full-mouth and sample site clinical periodontal parameters of all groups are shown in Table 1. In fullmouth, the mean PD values in the CP and RA-b groups were significantly higher than that in the HC group. The mean PD values in RA-a and RA-b were significantly lower than that in the CP group (p < 0.05). The mean GI, PI, GBTI and CAL values in the HC group were the lowest among the groups (p < 0.05).

RA-a: PD 6 3 mm, RA-b: PD > 3 mm PD: probing depth, GI: gingival index, PI: plaque index, CAL: clinical attachment level. a Statistically significantly different than the CP group p < 0.05. b Statistically significantly different than the HC group p < 0.05. c Statistically significantly different than the RA-b group p < 0.05. d Statistically significantly different than the RA-a group p < 0.05.

CAL (mm)

3.1. Clinical parameter values (full mouth)

1.36 ± 0.61a,b 1.5 ± 0.69b 1.40 ± 0.61b,d 0 ± 0a,d,c

GBTI PI

3. Results

1.43 ± 0.63a,b 1.52 ± 1.21b 1.46 ± 0.82b,d 0 ± 0a,d

Clinical parameter data and GCF IL-4 and IL-10 levels among the groups were compared using the independent samples t-test. The correlations between the GCF IL-4 and IL-10 levels and clinical parameter data in sample sites in all groups were examined by Pearson correlation analysis.

1.08 ± 0.90a,b 0.99 ± 0.65a,b 1.06 ± 0.082b,d,c 0 ± 0a,d,c

2.6. Statistics

1.70 ± 0.55a,b,c 4.73 ± 1.63b,d 4.82 ± 0.69b,d 1.07 ± 0.16a,d,c

low levels. The analysis of cytokines was made by use of ELISA.

2.55 ± 0.76a,b,c 4.92 ± 0.73 b,d 5.02 ± 0.46b 1.43 ± 0.70a,d,c

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RA-a (n = 12) RA-b (n = 5) CP (n = 17) HC (n = 17)

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F.Y. Bozkurt et al. / Cytokine 35 (2006) 180–185 Table 2 The correlations between the cytokines and the clinical parameters in sample sites Group

Correlations

R

RA-a RA-b CP

IL-4–IL-10 — IL-4–IL-10 IL-4–PI IL-10–PI —

0.737** — 0.701** 0.516* 0.494* —

HC

RA-a: PD 6 3 mm, RA-b: PD > 3 mm, GI: gingival index, PI: plaque index, CAL: clinical attachment level, PD: probing depth. * Correlation is significant at the 0.05 level. ** Correlation is significant at the 0.01 level.

†¶*

5

Concentrations(pg/µL)

4,5

±2.25

4 †¶*

3,5 3

±1.13

IL-4

2,5 2 1,5 1

IL-10

‡ †‡ ‡

±0.50

†‡

‡*

±0.43 ±0.34

¶‡

±0.22

±0.37

±0.31

0,5 0 RA-a

RA-b

CP

HC

Fig. 1. GCF IL-4 and IL-10 levels in RA, CP and healthy groups RA-a, PD 6 3 mm, RA-b, PD > 3 mm  : statistically significantly different than the CP group p < 0.05; à, statistically significantly different than the HC group p < 0.05; *, statistically significantly different than the RA-a group p < 0.05; –, statistically significantly different than the RA-b group p < 0.05.

4. Discussion RA and CP have remarkably similar pathobiology [32– 35]. The cell infiltration, enzymes and cytokines which determined the severity of tissue damage all share a common pathologic process in both RA and CP. For both diseases the host response, orchestrated by immunogenetics, determines the inflammatory responses [36–38]. The similarities between RA and CP have prompted several studies of periodontal status in patients with RA and CP and these studies have reported a significant association between RA and periodontal disease [6,33,34,38–40]. It has been suggested that the RA patients have less plaque and calculus than healthy subjects [34]. On the other hand, Mercado et al. [38], Yavuzyilmaz et al. [39] and Ka¨ßer et al. [6] have reported that there is a significant association between periodontitis and RA. In our previous study [3]; we could not detect a significant difference between the RA and CP groups in the mean clinical parameters data except PI. In the present study, we found more severe gingival inflammation in CP than the RA patients.

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In this study, we also studied the levels of IL-4 and IL10 in GCF both CP and RA. The IL-4 levels in HC were found significantly higher than the CP and RA groups. The level of IL-4 in RA-b group was found significantly higher than CP group. Parallel results demonstrated that the levels of the IL-10 in HC were also significantly higher than the CP and RA groups. While there was no significant difference between the CP and RA-b groups, IL-10 mean level in the RA-a group was statistically higher compared to the CP group. There are several studies in which have evaluated IL-4 levels in GCF. Salvi et al. [41] found lower Th2 cytokine levels than Th1 cytokines in GCF in periodontitis patients at terminal status. In addition, it has been suggested that the selective absence of IL-4, which enhances the accumulation of macrophages and the increase of the expression of CD14 plays a key role in rapid destruction of periodontal tissues [41]. Recently, IL-4 in GCF could not be detected in severe periodontitis patients. After the resolution of the inflammation, they could detect IL-4 and the decreases of IL-1 at those sites and they have suggested that IL-4 balances the inflammation with the decreasing effect on the synthesis of pro-inflammatory cytokines from macrophages [42]. In the present study, we also detected the lowest IL-4 level in CP patients. The pathogenesis of RA has been also found associated with the IL-4 levels. It has been reported that IL-4 inhibits lipopolysaccaride induced cytokines production by monocytes isolated from peripheral blood with RA patients, but only partially on monocytes isolated from RA fluid or synovial membrane [43]. IL-10 is also a potent anti-inflammatory mediator which acts by inhibiting the synthesis of pro-inflammatory cytokines and bone resorption in vitro [44–54]. Cutler et al. [54] reported that the improvement in clinical parameters were associated with decrease in pro-inflammatory cytokines and increase in IL-10 levels. It has been also suggested that lower amounts of IL-10 may contribute to disease progression and enhance the progression of gingivitis to periodontitis and this cytokine may be of fundamental importance in the control of periodontal disease [21,55,56]. The GCF IL-10 levels in CP and RA patients were found lower than the HC group in our study. The absence of IL-10 may give rise to the progression of the inflammation and the tissue destruction in RA patients. Besides, this result has led us to the considerate that IL10 may have an important role in the pathogenesis of periodontitis. The insignificant difference between the CP and RA-b groups may point out that the RA pathogenesis could be actually a model for the periodontitis and the clarification of the role of IL-10 may clarify the pathogenesis of periodontal diseases partially. In physiologic conditions, the actions of pro-inflammatory cytokines are maintained in balance by anti-inflammatory cytokines such as IL-4, IL-10, IL-11, IL-13 and by natural cytokine antagonists, including IL-1 receptor antagonist (IL-1ra), soluble TNF receptor. In our study, both IL-4 and IL-10 production were insufficient in both

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RA and CP patients compared to HC. The initiation and progression of inflammation in both RA and CP may be due to inappropriate response of the anti-inflammatory cytokines. It has been suggested that the disease progression seen in periodontitis consist of the high levels of pro-inflammatory cytokines including IL-1b and TNF-a and low levels of IL-10 and transforming growth factor b, cytokines that suppress the immunoinflammatory response as for RA [57]. This is the first report on IL-4 and IL-10 GCF levels and their correlations with the clinical parameters in RA patients. In RA patients, anti-inflammatory drugs may effect on the gingival inflammation, besides these drugs could change the synthesis of anti-inflammatory cytokines, IL-4 and IL-10, etc. The major limitation of this study is the lower patient numbers in each group, particularly in the RA-b group. However, in this preliminary report, the correlations between the cytokines and clinical parameters were presented, no cause-and effect have established. Future studies are required for higher number of patient and different probing depth categorizations. 5. Conclusion Our results show that the production of IL-4 and IL-10 are significantly lower in CP patients than HC. In addition, the levels of IL-4 in the CP group were also lower than RA-b group. An imbalance between pro- and antiinflammatory cytokines plays an important role in both diseases. Future studies should aim to investigate the mechanism of interactions between pro- and anti-inflammatory cytokine production at molecular and cellular levels at different stages of periodontal lesions in both CP and RA patients. Acknowledgments The authors are grateful to Ms. Nihal Yetkin, linguistic scientist, for her great assistance in the linguistic revision of the manuscript.

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