Indian Journal of Oral Health and Research

REVIEW ARTICLE
Year
: 2021  |  Volume : 7  |  Issue : 2  |  Page : 49--54

Interleukin-17: Is it a predictable biomarker for periodontal disease?


Chandran Preeja1, Arun Sivadas2,  
1 Associate Professor, Department of Dentistry, Sree Gokulam Medical College and Research Foundation, Venjaramoodu, Thiruvananthapuram, Kerala, India
2 Consultant Periodontist and Implantologist, Department of Dentistry, Sree Gokulam Medical College and Research Foundation, Venjaramoodu, Thiruvananthapuram, Kerala, India

Correspondence Address:
Chandran Preeja
Associate Professor, Department of Dentistry, Sree Gokulam Medical College and Research Foundation, Venjaramoodu, Thiruvananthapuram, Kerala
India

Abstract

Periodontal disease is a multifactorial disease affecting the supporting tissues of the teeth and many etiologic factors are implicated in etiopathogenesis of periodontal disease. Although pathogenic bacteria have been the main causative factor in periodontal disease, host response accounts for the majority of periodontal destruction by releasing various inflammatory mediators, which has a negative impact on the periodontium. The host immune responses are regulated by various classes of T-cell subsets. Initially, periodontal disease can be explained with the T-helper 1/T-helper 2 paradigm. However, the discrepancies associated with it have led to the discovery of T-helper 17, which is responsible for the secretion of the cytokine interleukin-17 (IL-17). IL-17 is mainly a proinflammatory cytokine associated with periodontal inflammation, but controversies still exist with regard to whether they have a protective or destructive role in periodontal disease. Thus, the emergence of IL-17 has opened a new perspective of periodontal disease pathogenesis, but more number of researches is needed in this field to consider IL-17 as a predictable biomarker for periodontal disease.



How to cite this article:
Preeja C, Sivadas A. Interleukin-17: Is it a predictable biomarker for periodontal disease?.Indian J Oral Health Res 2021;7:49-54


How to cite this URL:
Preeja C, Sivadas A. Interleukin-17: Is it a predictable biomarker for periodontal disease?. Indian J Oral Health Res [serial online] 2021 [cited 2022 Jun 28 ];7:49-54
Available from: https://www.ijohr.org/text.asp?2021/7/2/49/333381


Full Text



 Introduction



Periodontal disease is a chronic multifactorial disease involving the gingiva and the supporting structures of the tooth characterized by the loss of connective tissue attachment and destruction of supporting periodontal tissues. The primary local factor in the etiology of periodontal disease is bacterial plaque biofilm, and the treatment of periodontal disease is directed toward eliminating this bacterial plaque biofilm and calculus along with bacterial pathogens associated with periodontal disease. The main treatment modalities for periodontal disease include mechanical debridement, antimicrobial therapy, and recently host modulatory therapy.

In periodontal disease, tissue destruction occurs mainly by two mechanisms: direct periodontal destruction due to virulence factors from subgingival microorganisms and indirect periodontal destruction due to inflammatory mediators derived from the host. Indirect bone loss due to host response is more destructive than direct bone loss. The inflammatory mediators released due to host response include prostaglandins such as PGE2, interleukins (ILs) (e.g. IL-lα, IL-lβ, and IL-6), tumor necrosis factor alpha (TNF-α), and matrix metalloproteinases (MMPs), which are recruited into the periodontium resulting in destruction of periodontium. Hence, host response plays an important role in the pathogenesis of periodontal disease. The acquired or adaptive immune response comprising cellular and humoral immune responses is regulated by various T-cell subsets. T-helper (Th) cells are subpopulations of T-lymphocytes classified into T-helper 1 (Th1) and T-helper 2 (Th2) on the basis of cytokine secretion by Mosmann and Coffman in 1986.[1] These Th cells when primed with an antigen will produce soluble factors called cytokines consisting mainly of various classes of ILs. The main function of Th1 cells is the crucial role played in cell-mediated immunity by secreting interferon-gamma (IFN-γ) resulting in activation of macrophages, natural killer (NK cells), and cluster of differentiation 8 (CD8+) T-cells. The cytokines released from Th1 enhances antigen uptake and antigen presentation by stimulating the B-cells to secrete antibody isotypes. Humoral immunity is mediated by Th2 cells and it includes activation of mast cells by releasing immunoglobulin E, thereby playing a major role in allergic type response. The T-cell-mediated immunity and the immune response associated with almost all the diseases can be explained with the Th1/Th2 paradigm.[2] However, there are many controversies reported with this model and the emergence of a new class of T-cells termed “T-helper 17 (Th17)” has resolved many of the discrepancies associated with Th1/Th2 paradigm and opened up a new direction for periodontal research.[3],[4] Th17 is the source of secretion of IL17 which is the hallmark proinflammatory cytokine involved in the pathogenesis of periodontal disease. However, there is still a disagreement regarding whether IL-17 is having a protective or destructive role in periodontium. This review is mainly focused to explain the novel proinflammatory cytokine IL-17 secreted from Th17 cells and its role in periodontal disease which provides new insights into the pathogenesis of periodontal disease.

 Role of Cytokines in Periodontal Disease



The development of an effective host immune response against an infection requires interaction between various cells of immune system such as lymphoid cells, inflammatory cells, and hematopoietic cells. These complex interactions between cells are mediated by various types of molecules such as major histocompatibility complex, integrins, and cytokines. Cytokines are low-molecular-weight messenger proteins that act in an autocrine or paracrine manner. Cytokines are secreted mainly by white blood cells and various other cells in the body such as epithelial cells, dendritic cells, macrophages, fibroblasts, endothelial cells, and osteoblasts, and their main function is to elicit the secretion of various proinflammatory cytokines and chemokines by nonimmune cells. They are also involved in neutrophil trafficking to the site of inflammation and stimulate the production of antimicrobial peptides from keratinocytes enhancing barrier protection. Cytokines that regulate T-cells are mainly released from various T-cell subsets such as Th1, Th2, Th17, and T-regulatory (Treg) cells, and their main function is to maintain the balance of T-cell subsets, regulation of adaptive immunity, and enhancement of inflammatory responses. Cytokines produced by Th1 cells mainly mediate cellular immunity by secreting IFN-γ, IL-2, and TNF-β and Th2 cells mainly participate in allergic and humoral responses releasing IL-4, IL-5, IL-6, and IL-13. Another type of T-cell subset is Treg cell which arise in the presence of TGF-β, and its main function is to protect the body against inappropriate T-cell responses by secreting the cytokines IL-10, IL-35, and TGF-β. IL-35 has a profound immunosuppressive effect on Th1, Th2, and Th17 cells and also causes proliferation of Tregs.[5] IL-11 is another multifunctional cytokine which inhibits the production of proinflammatory cytokines such as TNF-α, IL-6, and IL-1 β in vitro and has been recently described as the regulatory cytokine within inflamed periodontal tissues.[6] Recently, a novel T-cell subset have been identified in many studies named Th17 producing the cytokines IL-17, IL-21, and IL-22.[5],[7] The secretion and regulation of Th17 cytokines are under the control of cytokines released from Th1 and Th2 cells. Th17 cells have an antagonizing effect on Treg cell development, thereby enhancing autoimmunity and proinflammatory responses.[8] The interplay between various T-cell subsets is essential for the regulation of immune response in the body. The knowledge about the new subset of T-cells and the inflammatory mediators released from it opens a new aspect of understanding the host defense mechanism, immune response, and pathogenesis of various diseases.

 T-helper 17 Response in Periodontal Disease



Th17 is a novel T-cell receptor mainly associated with chronic inflammatory conditions such as periodontal disease and is involved in the production of cytokines such as IL-17, IL-21, and IL-22.[5],[7] Th17 cells have a key role in generating a massive inflammatory response against extracellular bacterial and fungal infections, especially at mucosal interfaces. Thl7 response takes place in 3 steps: differentiation, stabilization, and amplification.[8] The differentiation of Th17 is due to the elevated expression of retinoic acid receptor-related orphan receptors (ROR)γ in native T-cells by TGF-β and IL-6.[7] Therefore, the key transcription factor in Thl7 development is RORγ. After the activation of Th17, it is amplified and stabilized by IL-21 and IL-23, respectively, and IL-23 plays a major role in maintaining the function of Th17.[9]

 Interleukin-17 Family and Receptors



IL-17 is a proinflammatory cytokine secreted by activated T-cells.

According to Moseley et al., IL-17 family includes other related molecules which are discovered subsequently through advanced methods. The main prototype of the family has been identified as IL-17A with five additional members designated as IL-17B, IL-17C, IL 17D, IL-17E (also known as IL-25), and IL-17F. The cognate receptors for the IL-17 family cytokines include IL-17R, IL-17RH1, IL-17RL (receptor like), IL-17RD, and IL-17RE.[10] Along with IL-17A, another member of IL-17 family expressed by Th17 includes IL-17F,[11] which generates same signals qualitatively by binding to the same receptor subunits as IL-17A,[12] but its affinity and signaling potency are found to be weaker. IL-17E is another member of IL-17 family of cytokines which may be a marker of disease severity, but it is having an opposing role to IL17A in the pathogenesis of periodontitis by negatively regulating the expression of IL-17A and eliciting the secretion of chemokines by oral keratinocytes.[13]

 Regulation of T-helper 17



The key factor in the regulation of Th subtypes is the competition between Thl and Th17. This is mainly by IFN-γ from Thl which inhibits the development of Th17 and Thl7 in turn secretes less IFN-γ to prevent the host from initiating a Thl response.[14] This competition is very crucial for the role of various Th subtypes in resorption of alveolar bone. The cytokines released from activated Th17 stimulate many other cells resulting in release of larger amounts of cytokines and chemokines. Furthermore, most of the proinflammatory cytokines responsible for bone resorption in periodontal disease like TNF-α, IL-1 β, and IL-6 are regulated by IL-17. The development of Th17 cells is downregulated by Treg cell forming the basis of how inflammation can provoke autoimmunity.

 Role of interleukin-17 in Periodontal Disease



ILs are a group of cytokines expressed by leukocytes. There are approximately 34 ILs described from IL-1 to IL-35 with IL-14 in doubt.[5] IL-17 is a proinflammatory cytokine released from activated Th17 cells.[15] Besides IL-17, TNF-α and IL-6 are released from Th17.[7] IL-17 plays a major role in immune response because it stimulates the secretion of various chemokines resulting in recruitment of neutrophils and macrophages causing the subsequent clearance of pathogens.[16] IL-17 mediates the actions of adaptive and innate immune systems resulting in proper regulation of immune response. Immune responses if not properly orchestrated can adversely affect the host which is manifested as bone destruction in periodontal disease. Evidence from various studies[17],[18] substantiated that the destruction of bone in periodontal disease is mainly by immune response of the host rather than due to infectious microorganisms. The interplay between osteoblasts and osteoclasts in bone remodeling has a crucial role in maintaining bone homeostasis. The differentiation of osteoclasts is under the control specific factors released from B and T lymphocytes. Another group of factors having a major impact in osteoclastogenesis is the receptor activator of nuclear factor kB (RANK) and RANK ligand (RANKL) which on binding induces the differentiation of osteoclasts favoring bone resorption.[19] Osteoprotegerin (OPG) is a soluble “decoy” receptor that has a bone protective action by binding with RANKL preventing its interaction with RANK. RANKL is activated by cytokines such as IL-17, IL-1 β, IL-6, and TNF-α and many studies have proved the role of IL-17 in bone remodeling favoring bone resorption. This is due to the modulation of RANKL/OPG ratio by IL-17 and also by increasing the expression of RANKL and decreasing the expression of OPG.[20],[21] Therefore, IL-17 released from Th17 cells opens a new perspective in the pathogenesis of periodontal disease.

Although IL-17 has a major role in periodontal pathogenesis whether they have a protective or destructive role in periodontal disease is still a matter of controversy.[22] According to Yu et al., IL-17 has a bone protective effect in periodontal disease due to its crucial role in neutrophil regulation.[23] This can be explained due to the fact that neutrophils form the first line of defense and they play an active role in controlling periodontal infection; hence, impairment of neutrophil function can lead to increased microbial load. There are evidences showing that inherited disorders in neutrophil chemotaxis are correlated with a high frequency of developing periodontal disease. In such cases there may be genetic polymorphisms affecting the expression of chemokines which inturn increases the susceptibility to periodontal disease.[24] In sterile inflammatory conditions such as rheumatoid arthritis or other autoimmune disorders, IL-17 can cause tissue destructive effects. However, in infectious inflammatory conditions such as periodontal disease, IL17 is having tissue protective actions due to its key role in the recruitment of neutrophils and other immune cells, thereby limiting the spread of periodontal infection.[25] Thus, Th17 cells play a key role against protection from bacteria and fungi which are not adequately dealt with Th1-mediated immunity.[26] However, there are various studies reporting elevated levels of IL-17 in the destructive phase of periodontal disease.[27] Another recent study implicated a destructive role of Th17 cells due to the fact that Th17 acts as an osteoclastogenic lymphocyte that links T-cell activation to bone resorption.[28] Therefore, IL-17 is a proinflammatory cytokine with dual action in various inflammatory disorders and further studies should be done in this field to evaluate the predominant role played by IL-17 in periodontal disease.

 Interleukin-17 and Periodontal Disease



IL-17 is a novel cytokine with many proinflammatory actions playing a major role in immune regulation of periodontal disease; hence, it is important to review its role in periodontal pathogenesis.

Criteria for including studies in this review

A literature search was conducted using PubMed central in addition to searching reference lists of original and review articles. The search strategy used was combination of the terms: “IL-17,” “Th17,” “cytokines,” and “periodontal disease.” The articles included were from 1985 to 2019. Human studies were included and animal studies were excluded in this review. Only English-language articles were considered, and unpublished data were not included.

Evidence for the role of interleukin-17 in periodontal disease

IL-17 has been recently implicated in the pathogenesis of periodontal disease and there are many studies in the literature documenting the presence of IL-17 in patients with periodontitis suggesting its role in mediating inflammatory reaction in periodontal disease. However, it is still controversial to consider it as a predictable biomarker for periodontal disease. The presence of IL-17 in periodontitis patients was reported by Yao et al. as early as in 1995.[15] After that, an in vitro study by Oda et al. reported the presence of IL-17 in patients with periodontitis. According to the results of this study, Porphyromonas gingivalis outer membrane protein can induce the production of IL-17 in patients with periodontitis, and after its stimulation, it is detectable in patients with periodontitis than in those with gingivitis.[27] The role of IL-17 in bone resorption was evaluated by Sato et al. and they demonstrated that Th17 cells are the important T-cell subsets involved in osteoclast formation as assessed by osteoclast formation in cocultures of Th cell subsets with bone marrow cells. But in cocultures with IFN-γ and IL-4 expressing Th1 and Th2 cells were found to be inhibitory. This study gives strong evidence that Th17 rather than Th1 as the specialized osteoclastogenic lymphocyte that links T-cell activation to bone resorption.[28] Another study by Takahashi et al. investigated for the presence of IL-17 in periodontal lesions and to determine the effect of IL-17 on IL-6 production in human gingival fibroblasts. They found that IL-17 is produced in periodontal lesions and is involved in Th1 modulation and also enhances inflammatory reactions through mediators from gingival fibroblast in periodontal disease.[29] Vernal et al. evaluated for the presence of IL-17 in gingival crevicular fluid (GCF) and from cell cultures of gingival tissue in patients with periodontitis and reported its presence in GCF and gingival cell cultures suggesting a role for IL-17 in periodontal pathogenesis.[30] The level of concentrations of IL-23 and IL-17 was assessed in a study by Lester et al. and found that the concentrations of IL-23 and IL-17 are elevated at sites with clinical attachment loss than at healthy sites.[31] Beklen et al. in their study reported that IL-17 acts as a key cytokine regulating MMP-1 MMP-3, IL-1, and TNF in periodontitis patients.[32] Another study confirmed the elevated expression of IL-17 and IL-23 in patients with chronic periodontitis indicating a major role for T cells in periodontal pathogenesis.[33] González et al. investigated the levels of IL-17 in GCF of patients with progressive chronic periodontitis and confirmed an elevated proportion of IL-17 in GCF.[34] A study was conducted by Ohyama et al. to assess the involvement of IL-23 and IL-17 in periodontitis patients and found an increased expression of these cytokines in periodontal lesions in areas adjacent to bone loss when compared to controls.[35] The relationship between Th17 cells and clinical inflammation was evaluated by Cardoso et al. and showed a positive correlation between Th17 cells and sites of chronic inflammation in periodontal disease.[36] Pradeep et al. did a study in Indian population to explore the role of IL-17 and IL-18 in periodontal disease progression and the effect of periodontal treatment on their concentration. The results of the present study indicate that IL-17 cannot be considered as a biomarker of periodontal disease progression due to its lack of detection in GCF and IL-18 appears to be an inflammatory biomarker for periodontal disease.[37] The expression of IL-17 and RANKL mRNA in progressive periodontal lesions was explored by Dutzan et al. and demonstrated an increased level in progressive lesions compared to quiescent lesions.[38] The role of IL-17 in aggressive periodontitis was investigated by Schenkein et al. and reported an increased level of IL-17 in the sera of patients with aggressive periodontitis, suggesting a potential role of IL-17 in the pathogenesis of aggressive periodontitis.[39] Adibrad et al. in their study reported an increase in the number of some specific markers of Th17 cells in patients suffering from periodontal disease in comparison with normal control subjects.[40] Awang et al. conducted a study to explore the clinical relationship between IL-17 family of cytokines and periodontitis and also to determine the roles of IL-17A and IL-17E in in vitro models. IL-17A and IL-17E with opposing actions play a crucial role in periodontal pathogenesis and may be a marker of disease severity. IL17E negatively regulates the expression of IL-17A and chemokines secretion induced by periodontal pathogens.[13] IL-35 plays an important role in immune regulation through the suppression of effector T-cell populations, including Th17 cells. The expression of IL-35, IL17, and IL-27 in GCF and gingival tissue was assessed in a study by Mitani et al. and they concluded that IL-35 and IL17 play a role in periodontal pathogenesis and IL-27 failed to show any role in periodontitis.[41] Another study done by Chen et al. investigated Th1/Th2/Th17 cytokine levels in plasma and GCF in chronic periodontitis patients and healthy controls. The results showed a stronger correlation between IL-17/IL-4 and IL-17/IL 10 in periodontitis patients than in healthy controls.[42] Cheng et al. in a review proposed the possible role of IL-17, and IL-17 producing CD4+ T cells (also called Th17 cells) in inflammatory periodontal disease. They suggested the crucial role of IL-17 and Th17 cells in periodontal disease and also the proof from animal studies, indicating the potential role in gingival inflammation and bone resorption in periodontitis.[43] The role played by IL-17 in leukocyte adhesion deficiency type I (LAD-1) patients with aggressive form of generalized periodontitis was mentioned in a review by Hajishengallis and Moutsopoulos. The aggressive form of periodontal destruction was initially attributed to defective neutrophil function, and now in a recent study, it has been shown that the severe periodontal destruction was due to dysregulation of host response which in turn leads to an increased expression of the cytokine IL-17, resulting in inflammatory changes and destruction of bone.[44]

 Interleukin-17 and Periodontitis in Diabetes Mellitus



The relationship between levels of IL-17 and TNF-α and type 2 diabetes mellitus was investigated in a study by Gursoy et al. and found that there is a positive correlation between periodontal disease severity and poor glycemic status, but the association between PPD and IL-17 level in saliva was independent of glycemic status.[45] A clinicobiochemical cross-sectional study was carried out by Prasad et al. to explore the link between IL-11, diabetes, and periodontitis. IL-11 reduces the expression of proinflammatory cytokines and periodontal tissue destruction by immune modulation, thereby having a protective role. Hence, in this study, the level of IL-11 was found to be reduced from healthy to periodontitis sites and was less in periodontitis group than in gingivitis group. The reduced level of IL-11 interprets the statement that both diabetes and periodontitis may play a synergistic role in the suppression of protective host responses.[46] Another study by Cheng et al. investigated the mechanism by which the periodontal pathogens of P. gingivalis and Aggregatibacter actinomycetemcomitans promote a Th17/IL-17 response in vitro and studied IL-17 + CD4 + T-cell frequencies in gingival tissue and peripheral blood from patients with PD versus periodontally healthy controls. The results from this study demonstrated the fact that periodontal pathogens can activate monocytes, resulting in increased IL-17 production by human CD4 + T cells, a process that appears enhanced in patients with periodontal disease.[47] A study by Niki et al. studied the role of IL_17 in the oral pathology of LAD-I patients or in LFA-1 (CD11a/CD18)-deficient mice. The study showed that LAD-I periodontal phenotype was associated with excessive production of predominantly T cell-derived IL-17 in the periodontal tissue. The pathological elevation of IL17 in the LFA-1-deficient periodontal tissue derived also from innate lymphoid cells. Furthermore, local treatment with anti-IL-17 (or anti-IL-23) in LFA-1-deficient mice not only blocked inflammatory periodontal bone loss but also caused a reduction in the total bacterial burden, suggesting that the IL-17-driven pathogenesis of LAD-I periodontitis leads to dysbiosis and support an IL-17-targeted therapy for this condition.[48] The density of IL-17 producing T cells and IL-17 mRNA expression in lesions representing severe periodontitis and longstanding gingivitis was analyzed in a study recently. The results of the study showed suggested that IL-17 producing T cells represent a significant feature in the detection of differences between destructive and nondestructive lesions and was higher in periodontitis than in gingivitis samples.[49]

 Role of interleukin-17 in Stem Cells



There are only a few studies in the literature specifically evaluating the role of IL-17 in stem cells. The role of IL-17 in bone remodeling was investigated by Lin et al. in 2014, and in their study, they concluded that IL-17 could significantly enhance the expression of receptor activator for nuclear factor-κB ligand (RANKL) and inhibit the expression of osteoprotegerin (OPG) in human periodontal ligament cells. This can lead to osteoclastogenesis resulting in bone resorption.[50] Another study recently explored the specific roles of IL-17 signaling cascades and osteocyte-specific pathways in the osteogenesis of mesenchymal stem cells (MSCs). The present study reported a synergistic effect of osteocytes and IL-17 in the production of biochemical signals to stimulate the osteogenic differentiation of MSCs, which could be further promoted in the PCL three-dimensional-scaffold implying a possible role of IL-17 in bone tissue engineering.[51] These are only a few studies focusing the association between IL-17 and stem cells and more number of studies should be carried out in future to throw light into this field.

 Conclusion



Evidence from current literature indicate that Th1 cells and the cytokines released from it are present in early/stable periodontal lesions, whereas Th2 cells are present during the phase of disease progression or in progressive periodontal lesions. The discovery of the new T-cell subset Th17 has led to a more vivid understanding of the host response in periodontal disease. The majority of studies done till date have proved that IL-17 has a potential role in etiopathogenesis of periodontal disease due to its effect on neutrophil mediated inflammation and promotion of osteoclastogenic effects accelerating periodontal destruction. Thus, more number of studies should be carried out to properly assess the role of IL-17 in periodontal disease, so that it can be considered as a predictable biomarker for periodontal disease. Furthermore, future therapeutic interventions in the field of periodontics should be based on the extended Th1/Th2/Th17 paradigm which will be able to optimize the treatment outcome after periodontal therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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