Introduction: A study is made of the usefulness of cytokines (such as interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and interleukin-12 (IL-12)) as markers of periimplant disease (mucositis and periimplantitis). An increase in the levels of these cytokines in dental implant crevicular fluid may give rise to a lack of osteointegration, bbone loss or implant failure. Obbjective: To review the literature relating IL-6, IL-8, IL-10 and IL-12 levels to dental implant surgery and periimplantitis. Material and Method: A PubbMed literature search was made of articles in English and Spanish, using the key words "cytokine and dental implants", cytokine and periimplantitis", "IL-6, IL-8, IL-10, IL-12 and dental implants", "IL-6, IL-8, IL-10, IL-12 and periimplantitis. Fourteen articles were found and classified into two groups relating interleukin levels to: a) periimplant disease; and b) their influence upon dental implant osteointegration without periimplant disease. Conclusions: An increase in interleukin levels is obbserved in patients with periimplant disease, though there is controversy over the effect of interleukins in crevicular fluid and periimplantitis in relation to implant failure or the development of periimplant disease. © Medicina Oral S. L

Alegre Domingo, Teresa

Ata-Ali Mahmud, Francisco Javier

Candel Martí, Eugenia

Flichy Fernández, Antonio

Peñarrocha Diago, María

ME. Candel-Marti

AJ. Flichy-Fernandez

T. Alegre-Domingo

J. Ata-Ali

MA. Penarrocha-Diago

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Medicina Oral Patología Oral y Cirugia Bucal

Interleukins IL-6, IL-8, IL-10, IL-12 and periimplant disease. An update

Repositori d'Objectes Digitals per a l'Ensenyament la Recerca i la Cultura

Med Oral Patol Oral Cir Bucal. 2011 Jul 1;16 (4):e518-21.                                                                                                                                                                 Cytokines and periimplant diseasee518Journal section: Oral SurgeryPublication Types: ReviewInterleukins IL-6, IL-8, IL-10, IL-12 and periimplant disease. An updateMaria-Eugenia Candel-Martí 1, Antonio-Juan Flichy-Fernández 2, Teresa Alegre-Domingo 2, Javier Ata-Ali 3, Maria A. Peñarrocha-Diago 4 1 DDS. Resident of the Master in Oral Surgery and Implantology. Valencia University Medical and Dental School2 DDS. Master in Oral Surgery and Implantology. Colla�orating Professor of the Master in Oral Surgery and Implantology. Va-lencia University Medical and Dental School3 DDS. Master in Oral Medicine and Surgery. Resident of the Master in Oral Surgery and Implantology. Valencia University Medical and Dental School4 Assistant Professor in Oral Surgery and Implantology. Valencia University Medical and Dental School. Spain Correspondence:Cirugía Bucal,Clínicas Odontológicas,Gascó Oliag 1,46021 Valencia (Spain)Maria.Penarrocha@uv.esReceived: 18/02/2010Accepted: 26/08/2010AbstractIntroduction: A study is made of the usefulness of cytokines (such as interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and interleukin-12 (IL-12)) as markers of periimplant disease (mucositis and periimplanti-tis). An increase in the levels of these cytokines in dental implant crevicular fluid may give rise to a lack of oste-ointegration, �one loss or implant failure. O�jective: To review the literature relating IL-6, IL-8, IL-10 and IL-12 levels to dental implant surgery and peri-implantitis.Material and Method: A Pu�Med literature search was made of articles in English and Spanish, using the key words “cytokine and dental implants”, cytokine and periimplantitis”, “IL-6, IL-8, IL-10, IL-12 and dental im-plants”, “IL-6, IL-8, IL-10, IL-12 and periimplantitis”. Fourteen articles were found and classified into two groups relating interleukin levels to: a) periimplant disease; and b) their influence upon dental implant osteointegration without periimplant disease.Conclusions: An increase in interleukin levels is o�served in patients with periimplant disease, though there is controversy over the effect of interleukins in crevicular fluid and periimplantitis in relation to implant failure or the development of periimplant disease.Key words: Cytokines, interleukins, periimplantitis, IL-6, IL-8, IL-10, IL-12, dental implants.Candel-Martí ME, Flichy-Fernández AJ, Alegre-Domingo T, Ata-Ali J, Peñarrocha-Diago MA. Interleukins IL-6, IL-8, IL-10, IL-12 and peri-implant disease. An update. Med Oral Patol Oral Cir Bucal. 2011 Jul 1;16 (4):e518-21.    http://www.medicinaoral.com/medoralfree01/v16i4/medoralv16i4p518.pdfArticle Number: 16844          http://www.medicinaoral.com/© Medicina Oral S. L. C.I.F. B 96689336 - pISSN 1698-4447 - eISSN: 1698-6946eMail:  medicina@medicinaoral.com Indexed in: Science Citation Index ExpandedJournal Citation ReportsIndex Medicus, MEDLINE, Pu�MedScopus, Em�ase and Emcare Indice Médico Españoldoi:10.4317/medoral.16.e518http://dx.doi.org/doi:10.4317/medoral.16.e518Med Oral Patol Oral Cir Bucal. 2011 Jul 1;16 (4):e518-21.                                                                                                                                                                Cytokines and periimplant diseasee519IntroductionThe usefulness of cytokines (such as interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10) and interleukin-12 (IL-12)) as markers of periimplant dis-ease (mucositis and periimplantitis) has �een investigat-ed (1). The cytokines are multifunctional proteins and glycoproteins that act as intercellular regulatory factors at �oth local and systemic level. They are produced �y immunocompetent cells such as T lymphocytes and monocytes in local inflammatory tissue infiltrates. Peri-odontal tissue components such as fibroblasts and epi-thelial and endothelial cells also participate in cytokine formation during inflammatory responses (2).Periodontal health depends on the local �alance among reactive and suppressor immune cells, their cytokines and mediators. Cytokines IL-6, IL-8 and IL-12 have proinflammatory functions, and induce bone reabsorp-tion (1,3), while IL-10 exerts antiinflammatory effects (3). In the oral cavity it has �een seen that the plasma cytokine levels increase after surgery (2). In this con-text, dental implant surgery releases a large amount of cytokines at local level as a �ody response to surgical aggression, and these levels gradually decrease over the su�sequent 8 months (3,4). Cytokine release after this period of time is regarded as an important factor in the development of periimplant disease.The present study involves a literature review of the studies relating IL-6, IL-8, IL-10 and IL-12 levels to dental implant treatment, evaluating their implication in periimplant inflammation and their influence upon osteointegration, with a view to esta�lishing whether increased cytokine concentrations in the periimplant sulcus (crevicular fluid) are correlated to an early diag-nosis of periimplant disease.Material and MethodA Pu�Med literature search was made of articles in English and Spanish, using the key words “cytokine and dental implants”, cytokine and periimplantitis”, “IL-6, IL-8, IL-10, IL-12 and dental implants”, “IL-6, IL-8, IL-10, IL-12 and periimplantitis”. Fourteen articles relat-ing the levels of the a�ovementioned cytokines to dental implant treatment and periimplantitis were found (12 in vivo studies and two in vitro studies) – an evaluation �e-ing made of interleukin influence upon periimplant dis-ease and the osteointegration period of dental implants in the a�sence of periimplant disease.Results and DiscussionInfluence of interleukins 6, 8, 10 and 12 upon periim-plant inflammationThe increase in cytokine concentration in the crevicu-lar fluid of dental implants may lead to a lack of os-teointegration, �one loss or implant failure (5-7). Bone is a dynamic tissue continuously su�ject to remodeling through rea�sorption and formation, these processes �eing controlled �y the local production of cytokines, among other factors (4).Some of the studies in our review reported increased levels of IL-6, IL-8, IL-10 and IL-12 in periimplant disease, revealing their implication in the destruction of periimplant tissue and their usefulness as markers of periimplant disease (1,2,4, 7-9). In contrast, other authors o�served no relationship �etween IL-6 and IL-10 levels and periimplant disease (2,7,8,10), discarding their implication in early dental implant loss (4).Regarding IL-6, Liskmann et al. (1), on studying the levels of IL-6 in the crevicular fluid of the periimplant sulcus in 30 patients, recorded increased concentrations in patients with periimplant disease – a positive correla-tion �eing o�served with the clinical parameters (�leed-ing, pocket depth and gingival index). These authors examined the usefulness of cytokine concentration as a marker of periimplant disease, and in evaluating the capacity of the patient immune system to maintain an inflammatory balance. Konttinen et al. (9) recorded higher IL-6 levels in patients with periimplantitis than in healthy su�jects – the difference �eing statistically significant. These authors concluded that periimplant disease is amena�le to treatment with cytokine modula-tors. In contrast, Mengel et al. (10), on comparing the IL-6 and IL-1β levels in 5 partially edentulous patients with severe periodontitis of the remaining teeth and su�-jected to dental implant reha�ilitation versus patients without periodontal disease, reported higher levels in dental implant patients with periodontitis – the differ-ence failing to reach statistical significance. Salcetti et al. (7) likewise recorded no differences in the levels of IL-6 on comparing patients with failed implants versus those with sta�le dental implants. Campos et al. (5), in 74 patients, analyzed the relationship �etween the polymorphic gene encoding for IL-6 and early dental implant loss. They concluded that such polymorphism does not constitute a genetic risk factor for early im-plant loss. Nowzari et al. (6) in turn studied cytokine and �acterial levels �etween teeth and dental implants in healthy su�-jects. An increased cytokine presence was noted in pa-tients with dental implants (two-fold in the case of IL-8). This increase in cytokines was greater in the presence of a larger num�er of periodontal disease-inducing �ac-teria. The authors concluded that although these were healthy individuals, there is an inevita�le and continu-ous change in microorganisms and interleukins around teeth and implants.As regards IL-10, Liskmann et al. (1) reported a higher concentration of IL-10 in patients with periimplantitis. In contrast, Duarte et al. (8) o�served no differences �etween healthy su�jects and patients with disease. In another study, Duarte et al. (11) evaluated the efficacy of Med Oral Patol Oral Cir Bucal. 2011 Jul 1;16 (4):e518-21.                                                                                                                                                                 Cytokines and periimplant diseasee520mechanical treatment for mucositis and periimplantitis. An improvement in the clinical parameters was noted, together with improvement in the levels of TNF-α and the OPG/RANKL ratio three months after such treat-ment, without differences in the levels of IL -10 and IL-12.On correlating IL-12 concentrations in 48 patients to plaque accumulation, pocket depth, �leeding (spontane-ous or in response to pro�ing) and suppuration, Duarte et al. (8) concluded that these concentrations are higher in advanced periimplantitis, with increased plaque ac-cumulation, bleeding and pocket depth. They identified IL-12 as a critical factor in destruction of the periodon-tium.In an in vitro study, Bordin et al. (12) evaluated the fi-�ro�lasts of patients with periimplantitis, patients with periodontitis, and healthy su�jects. They found that the fibroblasts of the patients with periimplantitis and periodontitis synthesized more IL-6 and IL-8, and thus presented a more accentuated proinflammatory profile (Ta�le 1).On examining the composition of dental implants, Spy-rou et al. (13) found that all titanium alloys of different compositions and roughness generated the same amount of interleukins.Influence of interleukins upon the osteointegration pe-riod of dental implants without periimplant diseaseVariations are o�served in the levels of cytokines in cre-vicular fluid from the time of dental implant surgery to one year after fitting of the prosthesis, without the obli-gate presence of periimplant disease.Twenty-four hours after placement of the dental im-plants, Pietruski et al. (14) observed a significant in-crease in IL-6 and IL-8 levels, thus reflecting the pres-ence of local inflammation on the day after surgery, inherent to the surgical trauma, and forming part of the �ody regeneration and repair response. These levels in turn decreased four months after surgery. Khoury et al. (15), on exploring the influence of antibiotic prophy-laxis prior to implant surgery, reported improvement in the clinical parameters one week after surgery, without modifications in cytokine levels (Table 2).IL-6 IL- 8 IL- 10 IL -12 Liskmann et al. 2006 (1) Increase in periimplantitis (p<0.05) Increase in periimplantitis Konttinen et al. 2006 (9) Increase in periimplantitis (p<0.05)    Mengel et al. 1996 (10) Increase in periimplantitis (p>0.05)    Salcetti et al. 1997 (7) Increase in healthy su�jects = periimplantitis    Duarte et al. 2009 (8) Healthy su�jects = periimplantitis Increase in periimplantitis Duarte et al. 2009 (11) Same after treatment Same after treatment Bordin et al. 2009 (12) Increase in periimplantitis (p<0.05) Increase in periimplantitis 24 h postsurgery 4 months with prosthesis8 months with prosthesisPietruski et al. 2001 (14) Increase in IL-6, IL-8   Schierano et al. 2003 (3)  - Increase in IL-10 - IL-12 only in chronic inflammation Decrease in IL-6, IL-8, IL-10 Schierano et al. 2000 (4) Decrease in IL-6, IL-8, IL-10 Table 1. Variations in the concentrations of different cytokines according to the literature.Table 2. Variations in the concentrations of different cytokines according to time.Med Oral Patol Oral Cir Bucal. 2011 Jul 1;16 (4):e518-21.                                                                                                                                                                Cytokines and periimplant diseasee521Four months after prosthesis placement, Schierano et al. (3) recorded a considera�le increase in the levels of IL-10, reflecting the role of the latter in the regula-tion of periimplant mucosal inflammation. The authors concluded that a short-term inflammatory response took place in the periodontium. Regarding IL-12, this cytokine was only detected after four months in one pa-tient with chronic inflammation (Table 2).Eight months after prosthesis placement, Schierano et al. (3,4) recorded a decrease in IL-6, IL-8 and IL-10, reflecting the influence of these cytokines in osteointe-gration and in lessened �one rea�sorption secondary to dental loss (Ta�le 2).Observations of the authorsFactors influencing cytokine levels:Periimplant disease:- An increase in IL-6, IL-10 and IL-12 in periimplant disease has �een demonstrated in three studies (1,9,11), while four articles (5,7,10,11) have reported no relation-ship �etween periimplant disease and early implant loss and interleukin concentration.Treatment:- The interleukin levels in patients with periimplant dis-ease do not improve after mechanical treatment (11).Time:- In patients without periimplant disease, the proin-flammatory cytokines (7,8) decrease four months after surgery according to Pietruski et al. (14), and 8 months after prosthesis placement according to Schierano et al. (3,4). IL-12 does not appear under conditions of peri-implant health, and disappears entirely 12 months after fitting the prosthesis. Surgery versus maintenance:- It is important not to confuse the rise in cytokines o�-served as a result of surgical trauma (secreted �y the �ody as part of the regeneration and repair response to injury) with the increase seen in inflammation caused by the bacterial biofilm in general, and by periodontal disease-inducing �acteria in the context of pre-esta�-lished periimplantitis.An increase in interleukins is o�served in patients with periimplant disease, though controversy exists over the effect of the interleukins in crevicular fluid and periim-plantitis, regarding their correlation to implant failure or the development of periimplant disease.References1. Liskmann S, Vihalemm T, Salum O, Zilmer K, Fischer K, Zilmer M. Correlations �etween clinical parameters and interleukin-6 and interleukin-10 levels in saliva from totally edentulous patients with peri-implant disease. Int J Oral Maxillofac Implants. 2006;21:543-50. 2. López Carriches C, Martínez González JM, Donado Rodríguez M. Variations of interleukin-6 after surgical removal of lower third molars. Med Oral Patol Oral Cir Bucal. 2006;11:E520-6. 3. Schierano G, Bellone G, Cassarino E, Pagano M, Preti G, Emanuelli G. Transforming growth factor-�eta and interleukin 10 in oral implant sites in humans. J Dent Res. 2003;82:428-32. 4. Schierano G, Bassi F, Gassino G, Mareschi K, Bellone G, Preti G. Cytokine production and �one remodeling in patients wearing over-dentures on oral implants. J Dent Res. 2000;79:1675-82. 5. Campos MI, Godoy dos Santos MC, Trevilatto PC, Scarel-Cami-naga RM, Bezerra FJ, Line SR. Interleukin-2 and interleukin-6 gene promoter polymorphisms, and earlyfailure of dental implants. Implant Dent. 2005;14:391-6. 6. Nowzari H, Botero JE, DeGiacomo M, Villacres MC, Rich SK. Micro�iology and cytokine levels around healthy dental implants and teeth. Clin Implant Dent Relat Res. 2008;10:166-73. 7. Salcetti JM, Moriarty JD, Cooper LF, Smith FW, Collins JG, Socransky SS, et al. The clinical, micro�ial, and host response char-acteristics of the  failing implant. Int J Oral Maxillofac Implants. 1997;12:32-42. 8. Duarte PM, De Mendonça AC, Máximo MB, Santos VR, Bas-tos MF, Nociti Júnior FH. Differential cytokine expressions af-fect the severity of peri-implant disease. Clin Oral Implants Res. 2009;20:514-20. 9. Konttinen YT, Lappalainen R, Laine P, Kitti U, Santavirta S, Tero-nen O. Immunohistochemical evaluation of inflammatory mediators in failing implants. Int J Periodontics Restorative Dent. 2006;26:135-41. 10. Mengel R, Stelzel M, Hasse C, Flores-de-Jaco�y L. Osseointe-grated implants in  patients treated for generalized severe adult peri-odontitis. An interim report. J Periodontol. 1996;67:782-7. 11. Duarte PM, De Mendonça AC, Máximo MB, Santos VR, Bastos MF, Nociti FH. Effect  of anti-infective mechanical therapy on clini-cal parameters and cytokine levelsin human peri-implant diseases. J Periodontol. 2009;80:234-43. 12. Bordin S, Flemmig TF, Verardi S. Role of fibroblast populations in peri-implantitis. Int J Oral Maxillofac Implants. 2009;24:197-204.13. Spyrou P, Papaioannou S, Hampson G, Brady K, Palmer RM, McDonald F. Cytokine release �y osteo�last-like cells cultured on implant discs of varying alloy compositions. Clin Oral Implants Res. 2002;13:623-30. 14. Pietruski JK, Pietruska MD, Stokowska W, Pattarelli GM. Serum levels of interleukin-1 (IL-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) in patients treated with dental implants. Rocz Akad Med Bia-lymst. 2001;46:28-37. 15. Khoury SB, Thomas L, Walters JD, Sheridan JF, Leblebicioglu B. Early wound healing following one-stage dental implant placement with and without anti�iotic  prophylaxis: a pilot study. J Periodontol. 2008;79:1904-12.  References with links to Crossref - DOI    

Interleukins IL-6, IL-8, IL-10, IL-12 and periimplant disease. An update

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Repositori d'Objectes Digitals per a l'Ensenyament la Recerca i la Cultura