白细胞介素17与牙周炎相关性的研究进展

牙周炎是由牙周致病菌所致的牙周组织慢性炎症性,破坏性疾病。IL-17是一种主要由T细胞产生的促炎因子,参与牙周炎的发生、发展,并可能与牙周炎严重性相关。本文就IL-17参与牙周炎症免疫应答反应及牙槽骨吸收的机制做一综述,旨在阐明IL-17参与牙周疾病的研究现状。     

Interleukin‐1 β, interleukin‐12 and interleukin‐18 levels in gingival fluid and serum of patients with gingivitis and periodontitis

Introduction: Cytokines are of major importance in periodontal disease progression. Interleukin‐12 (IL‐12) stimulates interferon‐γ production by T helper type 1 (Th1) cells while IL‐18 induces Th1 responses when present with IL‐12 but Th2 responses in the absence of IL‐12. IL‐1β has been correlated with periodontal disease destruction. This study determined the local concentrations of these cytokines in sites of gingivitis and periodontitis. Methods: Gingival crevicular fluid was collected from two sites in each of 10 gingivitis patients and from two gingivitis sites and two periodontitis sites from each of 10 periodontitis patients. Serum samples were also collected. IL‐1β, biologically active IL‐12 p70, the IL‐12 p40 subunit and IL‐18 concentrations were determined by enzyme‐linked immunoabsorbent assay. Results: IL‐1β and IL‐18 concentrations were higher in the gingival crevicular fluid from periodontitis patients than in that from gingivitis patients; IL‐18 concentrations were higher than those of IL‐1β. Very little IL‐12, either p40 or p70, was detected in the gingival crevicular fluid samples. In the serum, very low levels of cytokines were found. The level of serum IL‐12 p40, however, was higher than in the fluid from periodontitis sites of periodontitis patients. Conclusion: The local production of IL‐1β and IL‐18 in the gingival crevicular fluid increased with increasing inflammation and IL‐18 was the predominant cytokine at both gingivitis and periodontitis sites. Very little IL‐12 was detected with levels decreasing with increasing inflammation. These results suggest that there is an association between severity of periodontal disease and levels of IL‐1, IL‐12 and IL‐18.     

The presence,function and regulation of IL‐17 and Th17 cells in periodontitis

Periodontitis (PD) is a chronic inflammatory disease characterised by tissue inflammation and destruction of the associated alveolar bone. It is caused by the colonisation of the bacterial plaque biofilm and the resultant host immune responses in the surrounding periodontal tissues. The pro‐inflammatory cytokine IL‐17, and IL‐17 producing CD4+ T cells (also called Th17 cells) have been shown to play an important role in many inflammatory diseases. There is increasing evidence of the presence of IL‐17 and Th17 cells in human PD lesions and this may be associated with disease severity. Moreover, several animal studies indicate the potential role of IL‐17 and Th17 cells in gingival inflammation and the resultant bone destruction in PD. Here we review recent findings regarding the presence, function and regulation of IL‐17 and Th17 cells in PD, and we highlight potential areas of future research interest.     

Cytokine gene expression in chronic periodontitis

Background: Cytokines play an important rôle in controlling inflammatory processes and tissue homeostasis. Periodontitis, as any other chronic inflammatory disease, results from a disarrangement of host factors, mainly cytokines and the initiating agent. Modulation of the cytokines is not only controlled by the host but also by infecting bacteria and their products. Aim: In the present study, we examined the cytokine mRNA expression profiles in six patients, each presenting sites affected with (1) severe progressive periodontitis, (2) chronic, but stable periodontal lesions, and (3) with healthy sites. Analysis using a quantitative RT‐PCR included IFN‐γ, IL‐1β, IL‐2, IL‐4, IL‐5, IL‐6, and TNF‐α. Material and Methods: 6 patients with chronic periodontitis were following treatment observed for a period of six years for local sites staying healthy, local sites with periodontal pathology but without signs of progression of attachment loss and sites with verified progression were biosied. The biopsies were lyzed and analyzed for levels of cytokine mRNAs. Results: Results revealed considerable variation not only between patients, but also between individual sites. Each patient’s site has thus to be looked at as an independent entity. Conclusions: The local action of cytokines, which is heavily dependent on recruitment, interaction and activation of immunocompetent cells can explain the site‐specific nature of cytokine expression. Cytokine data from individual sites together with the local clinical status and data from the literature demonstrate the complexity of periodontal disease pathogenesis. To gain insight to specific mechanisms further studies are needed.     

Long‐term testosterone depletion attenuates inflammatory bone resorption in the ligature‐induced periodontal disease model

1 Background

Testosterone is known to affect bone in physiological and pathological conditions. The purpose of this study is to evaluate the role of testosterone in experimental periodontal disease in rats.

2 Methods

In this study we used a ligature model of periodontal disease in rats submitted to orchiectomy (OCX, testosterone depletion) with and without testosterone replacement therapy (TR). Control animals were sham‐operated and retained physiological testosterone levels. Sixty‐two days after orchiectomy and sham operations, ligatures were placed around the lower first molars for 2 weeks to induce experimental periodontal disease. Negative control animals received no ligatures. The outcomes assessed in the periodontal tissues were: inflammatory cytokine expression by enzyme‐linked immunosorbent assay (ELISA), stereometric analysis of the inflammatory process and quantitation of inflammatory bone resorption by microcomputed tomography (μ‐CT).

3 Results

The OCX+TR group showed the greatest increase in fibroblastic cells and blood vessels with reduced inflammatory cell numbers in the gingival tissue with induction of periodontal disease. There were no significant differences between OCX and Sham‐operated groups in all the stereometric parameters assessed. Ligature placement induced inflammatory bone resorption, which was significantly attenuated in OCX animals. Experimental periodontitis induced a significant increase in interleukin (IL)‐1β, but the lowest levels were observed in the periodontitis/OCX group. IL‐6 levels were not affected by OCX, but were significantly reduced in OCX+TR animals.

4 Conclusion

The findings of the present study suggest that testosterone depletion attenuates inflammatory bone resorption in ligature‐induced periodontitis, which may be partly mediated via decreased production of IL‐1β.     

TNF-α/ NF-κB信号通路对牙周炎发展和牙周再生的影响及其干预

牙周病是以菌斑微生物为始动因子的感染性疾病,菌斑微生物可刺激宿主细胞产生炎性和免疫因子,其中肿瘤坏死因子-α（tumor necrosis factor alpha,TNF-α）作为一个多向性的先导感染细胞因子,在牙周炎的发生、发展过程中起重要作用,同时也是牙周再生的重要影响因素。龈沟液中TNF-α水平的变化已经被用来作为牙周炎治疗的效果以及判断预后的重要指标,越来越多的研究开始关注以TNF-α作用过程为靶点探讨牙周炎发展控制和牙周再生促进的有效方法。本文就TNF-α/NF-κB信号通路对牙周病发展和牙周再生的影响及其干预治疗现状作一综述,以期为牙周病治疗提供新思路。     

Basic biology and role of interleukin‐17 in immunity and inflammation

Interleukin‐17 (also known as interleukin‐17A) is a key cytokine that links T‐cell activation to neutrophil mobilization and activation. As such, interleukin‐17 can mediate protective innate immunity to pathogens or contribute to the pathogenesis of inflammatory diseases, such as psoriasis and rheumatoid arthritis. This review summarizes the basic biology of interleukin‐17 and discusses its emerging role in periodontal disease. The current burden of evidence from human and animal model studies suggests that the net effect of interleukin‐17 signaling promotes disease development. In addition to promoting neutrophilic inflammation, interleukin‐17 has potent pro‐osteoclastogenic effects that are likely to contribute to the pathogenesis of periodontitis, rheumatoid arthritis and other diseases involving bone immunopathology. Systemic treatments with anti‐interleukin‐17 biologics have shown promising results in clinical trials for psoriasis and rheumatoid arthritis; however, their impact on the highly prevalent periodontal disease has not been investigated or reported. Future clinical trials, preferably using locally administered interleukin‐17 blockers, are required to implicate conclusivelyinterleukin‐17 in periodontitis and, more importantly, to establish an effective adjunctive treatment for this oral inflammatory disease.     

Porphyromonas gingivalis antigen preferentially stimulates T cells to express IL‐17 but not receptor activator of NF‐κB ligand in vitro

Although T cells have been implicated in the pathogenesis and are considered to be central to both their progression and control of chronic inflammatory periodontal diseases, the precise contribution of T cells to tissue destruction has not been fully clarified. Recently, interleukin (IL)‐17 and receptor activator of Nuclear factor κB NF‐κB ligand (RANKL) have received much attention as a result of their proinflammatory and bone metabolic roles, respectively. We therefore investigated the effect of outer membrane protein (OMP) from Porphyromonas gingivalis (P. gingivalis) on the expression of IL‐17 and RANKL in peripheral blood mononuclear cells (PBMCs) and compared these between gingivitis and periodontitis, which are representative of stable and progressive lesions, respectively. The in situ expression of these molecules was also examined. P. gingivalis OMP stimulated PBMCs to express IL‐17 at both the mRNA and protein level. Although the mean expression of mRNA was not different between the two groups, the mean level of IL‐17 in the culture supernatants was higher in gingivitis patients than in periodontitis patients. However, the frequency of IL‐17‐positive samples was higher in the periodontitis patients. This stimulatory effect was not evident for RANKL expression in either periodontitis or gingivitis patients. In gingival tissue samples, IL‐17 mRNA was detected in gingivitis more frequently than in periodontitis. The expression of RANKL mRNA was much lower than that of IL‐17 in terms of both level and frequency. These results suggest that IL‐17 but not RANKL may be involved in the pathogenesis of periodontal diseases. However, there may be negative regulatory mechanisms for IL‐17 in gingivitis.     

The role of natural killer cells in periodontitis

Periodontitis is the most common chronic inflammatory disease of humans. The microbial etiology of the disease is well documented, as is the major role of the host response in disease pathogenesis. As natural killer cells are one of the most important components of innate immunity against bacteria and viruses, they can be expected to act as major players in the development of the disease. Through direct interaction with periodontal pathogens, natural killer cells produce pro‐inflammatory cytokines that subsequently may lead to tissue destruction. Indeed, using a murine periodontitis model, such mechanisms have been shown to be involved in bacterial‐induced alveolar bone loss. In the present review we document the available literature and evidence base regarding the origin, biology and characteristics of natural killer cells, and their interactions with periodontal pathogens. The potential role of natural killer cells in periodontal pathogenesis and the mechanisms involved are discussed.     

Divergence of the systemic immune response following oral infection with distinct strains of Porphyromonas gingivalis

Periodontitis is a polymicrobial oral infection characterized by the destruction of tooth‐supporting structures that can be linked to systemic diseases such as cardiovascular disease, diabetes or rheumatoid arthritis. Porphyromonas gingivalis, a bacterium implicated in the etiology of periodontitis, has shown variation in inducing T‐cell responses among different strains. Therefore, in this study we investigated the strain‐specific immune response using a murine experimental model of periodontitis. Periodontitis was induced by P. gingivalis strains A7A1‐28, W83 and W50, and later confirmed by the presence of P. gingivalis in the oral microflora and by alveolar bone resorption. Splenocytes were evaluated for gene expression, cellular proteins and cytokine expression. Dendritic cells were stimulated in vitro for T helper cell–cytokine profiling. Results showed that P. gingivalis had the ability to alter the systemic immune response after bacterial exposure. Strains W50 and W83 were shown to induce alveolar bone loss, whereas the A7A1‐28 strain did not significantly promote bone resorption in mice. Splenocytes derived from mice infected with strains W50 and W83 induced expression of high levels of interleukin‐4 (IL‐4) but A7A1‐28 stimulated increased IL‐10. Stimulation of dendritic cells in vitro showed a similar pattern of cytokine expression of IL‐12p40, IL‐6 and transforming growth factor‐β among strains. A distinct systemic response in vivo was observed among different strains of P. gingivalis, with IL‐10 associated with the least amount of alveolar bone loss. Evaluation of pathogen‐driven systemic immune responses associated with periodontal disease pathogenesis may assist in defining how periodontitis may impact other diseases.     

Activation of interleukin 1β gene transcription by human cytomegalovirus: molecular mechanisms and relevance to periodontitis

In recent years, studies have demonstrated an association between human cytomegalovirus (HCMV) and destructive periodontal disease. It has been shown that reactivation of HCMV in periodontitis lesions may be related to progressing periodontal disease. Several possible mechanisms by which HCMV exerts periodontopathic potential have been previously proposed. These are reviewed and include the upregulation of bone resorptive cytokines such as interleukin‐1beta (IL‐1β) and tumor necrosis factor‐alpha (TNF‐α) by active HCMV infection at the periodontitis site. This review focuses on the molecular basis of IL‐1β gene activation by HCMV immediate early (IE) gene products. A novel hypothesis is also described whereby HCMV plays a significant role in the pathogenesis of periodontal disease by the ability of its IE proteins to strongly transactivate IL‐1β gene expression. More studies are needed to further explore this hypothesis and clarify the association between HCMV and periodontitis.     

Th17细胞在牙周炎中的研究进展

牙周炎是以牙周组织炎症和牙槽骨破坏为主要特征的慢性炎症性破坏性疾病。近来研究发现Th17细胞存在于牙周炎的病变牙周组织中,提示Th17细胞参与牙周炎的发病过程。本文就Th17细胞在牙周炎发病中的作用进行综述。     

The Presence and involvement of interleukin‐17 in apical periodontitis

Apical periodontitis (AP) is a chronic inflammatory disease characterized by periapical tissue inflammation and destruction of the associated alveolar bone. It is caused by microbial infections within the root canal and the resultant host immune responses in the periapical tissues. The proinflammatory cytokine interleukin (IL)‐17 has been shown to play an important role in many inflammatory diseases. There is increasing evidence of the presence of IL‐17 in AP, which might be associated with disease pathogenesis. Moreover, several animal studies indicate the potential role of IL‐17 in periapical inflammation and the resultant bone resorption in AP. This article reviews recent studies regarding the collective in vitro, in vivo and clinical evidence of the presence and involvement of IL‐17 in AP. A search related to IL‐17 in apical periodontitis was conducted on PubMed, EMBASE and Web of Science databases using keywords and controlled vocabulary. Two independent reviewers first screened titles and abstracts and then the full texts that were included. A total of 25 papers were identified, of the 25 included articles, 7 involved laboratory studies on cell cultures, 11 involved animal experimentations, and 7 were observational studies using human clinical samples. In conclusion, evidence for the presence of IL‐17 in AP from human and animal models is clear. However, there is relatively little information currently available that would highlight the specific role of IL‐17 in AP.     

The role of autophagy in the pathogenesis of periodontal disease

Periodontal disease is a chronic inflammatory disease leading to destruction of periodontal tissues. As a local inflammation, periodontopathic bacterium, pro‐inflammatory mediators, and local immune response play pivotal role in the progress of periodontal disease. Besides, cigarette smoke has long been associated with periodontal disease and tooth loss. Autophagy is an intracellular degradation process highly conserved from yeast to humans. As a lysosomal degradation pathway of self‐digestion, it is critical for maintaining cells homeostasis and development. The role of autophagy has been investigated in oral diseases, such as oral cancer, periapical lesions, and oral candidiasis. Recently, increasing studies investigated the role of autophagy in periodontal disease. In this review, we try to illustrate the effect of autophagy on periodontal disease pathogenesis from 5 aspects: autophagy affects the intracellular infection and survival of bacteria; autophagy has an interaction with periodontal inflammation; autophagy is pivotal in periodontal cells biology and periodontal tissues destruction and reconstruction; autophagy can be induced by cigarette smoke; last but not least, autophagy may affect periodontal disease via endoplasmic reticulum stress.     

The role of cytokines in a Porphyromonas gingivalis‐induced murine abscess model

Introduction: Porphyromonas gingivalis is an important periodontopathic bacterium that is strongly associated with periodontal disease and is part of human dental plaque. Periodontal disease results from the interaction of the host with bacterial products, and T‐cell‐derived cytokines remain critical in the immunoregulation of periodontal disease. Methods: The aim of this study was to examine the role of T helper type 1 [interleukin‐12p40 (IL‐12p40), interferon‐γ, tumour necrosis factor (TNF)] and type 2 (IL‐4, IL‐10) cytokines in the immune response to a subcutaneous challenge with P. gingivalis using a well‐established murine abscess model, in genetically modified cytokine‐specific knockout mice. Results: IL‐12p40^−/− mice exhibited more advanced tissue destruction and a reduced inflammatory cell infiltrate after subcutaneous P. gingivalis challenge. Deficiency of IL‐4 or IL‐10 did not result in increased susceptibility to P. gingivalis‐mediated tissue destruction. Furthermore, TNF deficiency appeared to reduce local tissue destruction. Interestingly, serum‐specific antibodies suggested a strong T helper type 2 response. Conclusion: The results of our study indicate an important role for IL‐12 in a primary P. gingivalis subcutaneous challenge.     

Periodontal and Systemic Responses in Various Mice Models of Experimental Periodontitis: Respective Roles of Inflammation Duration and Porphyromonas gingivalis Infection

Background: The great variability of periodontal and systemic responses to experimental periodontitis reflects the inherent pathogenic complexity of mice models and could limit the resulting interpretations and their extension to human diseases. This study compared the effect of Porphyromonas gingivalis (Pg) infection and experimental periodontitis duration at local and systemic levels in various models. Methods: Periodontitis was induced in C57BL/6J mice by ligatures previously incubated with Pg (LIGPG group) or not (LIG group) or by oral gavage (GAV) with Pg ATCC 33277. Blood samples were taken, and mice were euthanized at different times. Periodontal tissue destruction, osteoclast number, and inflammation were assessed by histomorphometry, tartrate‐resistant acid phosphatase histoenzymology, and cathepsin B (CATB) and matrix metalloproteinase 9 (MMP9) immunochemistry. Serum levels of interleukin‐6 (IL‐6) and IL‐1β were measured using enzyme‐linked immunosorbent assay bioplex methods. Results: Periodontal tissue destruction and osteoclast numbers were significantly elevated in LIGPG models compared to LIG and GAV models. They increased with time with the exception of osteoclast numbers in the LIG model. CATB and MMP9 expression was related to bone destruction processes and Pg infection. The highest serum levels of IL‐6 and IL‐1β were observed in the LIGPG group. A decrease of IL‐6 and an increase of IL‐1β serum level were observed with time in LIGPG group contrary to LIG group. Conclusions: These data indicate that Pg infection worsened periodontal tissue destruction through specific pathogenic pathways and modified systemic response to periodontal inflammation. Furthermore, the blood cytokine response to ligature models showed their relevance for evaluating the systemic impact of periodontal disease.     

Influence of sex steroids on inflammation and bone metabolism

Sex steroids are central to sexual development and reproduction, exerting pleiotropic effects on multiple tissues and organs throughout the lifespan of humans. Sex steroids are fundamental to skeletal development, bone homeostasis and immune function. The composite effect of sex‐specific genetic architecture and circulating levels of sex‐steroid hormones closely parallels differences in the immune response and may account for corresponding sex‐related differences in risk for chronic periodontitis, with men exhibiting greater susceptibility than women. Age‐associated reductions in sex steroids also provide insight into apparent temporal increases in susceptibility to periodontitis and alveolar bone loss, particularly among women. Chronic infection and inflammatory conditions, such as periodontal disease, provide a unique platform for exploring the interface of sex steroids, immunity and bone metabolism.     

Odanacatib,A Cathepsin K‐Specific Inhibitor,Inhibits Inflammation and Bone Loss Caused by Periodontal Diseases

Background: Periodontitis is a bacteria‐induced inflammatory disease mainly affecting periodontal tissues, leading to periodontal inflammation, bone breakdown, and loss of the tooth. The main obstacle for treating periodontitis effectively is the difficulty in finding a target that can inhibit bone loss and inflammation simultaneously. Recent studies showed that cathepsin K (CTSK) might have functions in the immune system besides its role in osteoclasts. Thus, targeting CTSK would have a potential therapeutic effect in both the bone system and the immune system during the progression of periodontitis. Methods: In the current study, a small molecular inhibitor (odanacatib [ODN]) is explored to inhibit the function of CTSK in a bacteria‐induced periodontitis mouse model. Results: The application of ODN decreased the number of osteoclasts, macrophages, and T cells, as well as the expression of Toll‐like receptors (TLRs) in the periodontitis lesion area. Furthermore, lack of CTSK inhibited the expression of TLR4, TLR5, and TLR9 and their downstream cytokine signaling in the gingival epithelial cells in periodontitis lesions, demonstrating that the innate immune response was inhibited in periodontitis. Conclusion: The present results show that inhibition of CTSK can prevent bone loss and the immune response during the progression of periodontitis, indicating that CTSK is a promising target for treating inflammatory diseases such as periodontitis by affecting both osteoclasts and the immune system.