The Role of Inflammatory Cytokines and Interleukin-6 ... · Chronic Periodontitis (CP) is a chronic inﬂammatory pathological condition caused by the interaction between microorganisms

Journal of Clinical Case Reports and Medical Research Review Article

Article Id: JCCRMR-20-04

The Role of Inflammatory Cytokines and Interleukin-6

Expression /Gene Polymorphism in Chronic Periodontitis:

Review of the Literature

Nikolaos Andreas Chrysanthakopoulos* *Dental Surgeon, Resident in Maxillofacial and Oral Surgery, 401 General Military Hospital of Athens, Athens, Greece

*Oncologist, Specialized in Clinical Oncology, Cytology and Histopathology, Department of Pathological Anatomy, Medical

School, University of Athens, Athens, Greece

Abstract

Periodontitis is a chronic inflammatory condition of the periodontal

tissues involving interactions between bacterial products,

inflammatory mediators, and various cell populations. It is accepted

that periodontitis is initiated by the dental plaque formation on the

teeth surfaces. Dental plaque ingredients such as antigens,

lipopolysaccharides, and other factors, initiate an inflammatory and

immune response, leading to the activation of host cells which results

in the release of inflammatory mediators such as cytokines,

chemokines, arachidonic acid metabolites and proteolytic enzymes

which contribute to tissue destruction and bone resorption. Recent

research regarding the pathogenesis of periodontal diseases has

clarified the involvement of various cytokines in the biological

activities that are implicated in its pathogenesis. Cytokines play

crucial roles in the maintenance of tissue homeostasis, whereas

excessive or continuous cytokines production in inflammatory

periodontal tissues is responsible for the progress of periodontitis and

periodontal tissue destruction. Inflammatory cytokines-such as IL-6,

IL-13, and IL-8 are present in the damaged periodontal tissues, and

their production is involved in chronic leukocyte recruitment, tissue

and bone destruction. It is possible that cytokine production and

expression may result to diagnose an individual's periodontal disease

status or susceptibility to the disease. Moreover, despite the

contradictory suggestions, it has been proposed that T-cell subsets Thl

and Th2 with different cytokine profiles play crucial roles in the

immunopathogenesis of periodontal disease. Chronic periodontitis is

suggested to be related to gene variations whereas; genetic variations

which are observed in cytokines may affect periodontitis

susceptibility. The aim of the current review was to present the role of

inflammatory cytokines and Interleukin-6 expression and its gene

polymorphism in chronic periodontitis pathogenesis.

*Corresponding author:

Dr. Nikolaos Andreas

Chrysanthakopoulos, University

of Athens, 35, Zaimi Street, PC

26 223, Patra, Greece, Tel./Fax:

0030-2610-225288; E-mail:

[email protected],

[email protected]

Received: 12 June 2020

Accepted: 04 July 2020

Published: 08 July 2020

Citation:

Chrysanthakopoulos NA. The

Role of Inflammatory Cytokines

and Interleukin-6 Expression

/Gene Polymorphism in Chronic

Periodontitis: Review of the

Literature. J Clin Case Rep Med

Res 2020;1:04

Copyright:

Chrysanthakopoulos NA. This

article is an open access article

distributed under the terms and

conditions of the Creative

Commons Attribution (CC-BY)

license

mailto:[email protected]

mailto:[email protected]



Keywords: Interleukin-6, single nucleotide polymorphism, chromic periodontitis, genotype

Introduction

Periodontal Disease (PD) affects nearly 50.0% of adults in the United States, whereas 8.5% of those have

been diagnosed with severe periodontitis. In addition, PD is regarded as one of the most common diseases

worldwide, showing a prevalence of 10%-15% (1). Risk of PD initiation and progression is associated

with smoking history, diabetes mellitus, age, poor oral hygiene, furcation involvement, residual pocket

depths, frequency of supportive periodontal care and genetics (2-6).

Periodontal pathogens that have been shown to be responsible for the PD initiation and progression, are

mainly Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, and are considered

the most important pathogens in periodontitis (7,8). Periopathogen products initiate an inflammatory

reaction that leads to local tissue destruction including connective tissue and bone support loss, which

may eventually result in tooth loss (9). The toxic products of the subgingival periopathogens disrupt the

immune surveillance and enhance the toxic environment of the periopathogens leading to a disruptive

tissue homeostasis which concerns connective tissue, periodontal ligament, cementum and alveolar bone

(10). The inflammation progression induces the production of insistent inflammatory signals by the cells

of periodontal tissues. Such signals, which involve the proinflammatory cytokines, IL-1,-2, and Tumor

Necrosis Factor-alpha (TNF-α) induce the production of secondary inflammatory mediators which in turn

amplify the inflammatory signalling pathways, that are able to lead to an increased production of

proteases and osteoclastic signals that result in connective tissue and bone destruction (11,12).

Chronic Periodontitis (CP) is a chronic inflammatory pathological condition caused by the interaction

between microorganisms that produce supragingival and subgingival biofilms and the host inflammatory

response (13), and is characterized by the inflammatory gingiva and the destruction of tooth-supporting

structures (14). CP etiopathogenesis involves many factors such as environmental and genetic factors (15-

18). The development of CP is promoted by the interaction between periodontal pathogens and the host

immune response (13,19). Host immune re-sponse of the periodontal tissues is caused by bacterial

infection, whereas, the inflammatory response of the periodontal tissues is influenced by environmental

and genetic factors (15,20). Concerning the genetic factors, cytokine genes may play an important role in

the immune pathology of PD and their analysis of polymorphisms may be possibly associated with it (21).

Those gene polymorphisms may cause an alteration in the encoded cytokine, or its expression, possibly

resulting in alterations in innate and adaptive immunity, and may hence be a definitive factor of PD

outcome determination (22,23).

One of the most investigated cytokines genes whose polymorphisms are associated with PD development

is IL-6. That cytokine shows various cellular functions, including differentiation and activation of

macrophages and T-lymphocytes and development and final differentiation of B-lymphocytes. IL-6 levels

regulation plays a crucial anti-inflammatory role in both systemic and local inflammatory reactions (24).

Previous reports have shown associations between IL-6 gene polymorphisms and periodontitis in different

ethnicities and it has been proposed that IL-6 -174G/C polymorphism is associated with periopathogens



identification, variations in inflammation severity, attachment loss and tissue destruction in PD (25,26).

Individual changes IL-6 blood levels may modify the predisposition to many inflammatory diseases, such

as PD, as it is a proinflammatory mediator that activates host cells and may lead to extracellular matrix

destruction. Such IL-6 changes are regulated by common nucleotide variations in its encoding gene,

which is located on chromosome 7p21 (27).

Pathogenesis of Periodontitis

Periodontitis has been considered to be a complex interaction between the bacterial invasion and the host

response, as already mentioned, which alters connective tissue and bone metabolism and causes

periodontal damage, as clinical attachment loss (28). PD consists of two main pathological conditions,

gingivitis and periodontitis and is a progressive condition, which leads to supporting tissue destruction

and in case of periodontitis leads to alveolar bone loss. Severe periodontitis and edentulism influence 743

and 158 million individuals worldwide, respectively (29,30). Gingivitis, is characterized by inflammation

of the gingival tissue, while in susceptible individuals, gingivitis may progress to periodontitis (23).

Although periopathogens are responsible for the PD initiation, the host immune response is implicated in

its pathogenesis as it seems to play a crucial role in the destruction of connective tissue and bone. The

mentioned immune and inflammatory reaction differs among individuals due to individuals genetic

factors as their susceptibility, environmental factors and possible polymorphisms in cytokines and

chemokines that are implicated in those reactions. Bacterial antigens and toxic agents, such as

lipopolysaccharides (LPS), peptidoglycans, lipoteichoic acids, proteases and toxins released by bacteria,

are recognized by toll like receptors (TLRs) on the surface of host cells, induce an immune and

inflammatory reaction, in which innate and adaptive immune systems are involved (31,32). The host

response to the bacterial invasion includes the stimulation of various inflammatory cell types such as

polymorphonuclear leukocytes (PMN), monocytes, macrophages, B- and T-lymphocytes (28,33). The

inflammatory reaction activates mast cells which in turn release vasoactive amines, TNF-α, and various

inflammatory mediators that are able to increase vascular permeability and the expression of adhesion

molecules such as inter-cellular adhesion molecule-1 (ICAM-1) and P-selectin on endothelial cell

surfaces. PMNs are recruited into the damaged tissue, and release lysosomal enzymes, such as

glycosidases, proteases, sulfatases which contribute to connective tissue breakdown (34). Despite the fact

that macro-phages and lymphocytes contribute to the destruction of a rate of 60-70% of the collagen in

the gingival connective tissue, no alveolar bone resorption is observed at that phase (35). The gingival

tissues damage at this phase is still reversible and it is possible to be repaired and restored after removal

of the etiological factors. However, in some cases the inflammatory reaction fails to resolve and

macrophages form preosteoclasts which, after maturing into osteoclasts are responsible for the

irreversible alveolar bone loss, due to innate susceptibility and/or environmental factors (36). Another

implication of an unsolved inflammatory reaction is that the bacterial antigens interact with antigen

presenting cells (APC) such as dendritic cells, macro-phages and B-lymphocytes. The interaction between

naive CD4 (+) T helper cells (T0) with APC, leads to the differentiation of those into various subsets of

cells including Th1, Th2, Th17 and regulatory T cells (Tregs), and this differentiation depends on the



cytokines that they produce, such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17, IL-22, IL-23, TNF-

α, TGF-β, IFN-γ, etc. Th1 cells are responsible for initiation of the cell-mediated immune response and

release IFN-γ, TGF-β, IL-2, and TNF-α in the presence of IL-12, which is released by dendritic cells,

macrophages and PMNs cells. Th2 cells are responsible for the humoral immune response and release the

cytokines IL-4, IL-5, IL-6, IL-10, IL-13 and TGF-β in the presence of IL-4. Th17 subset of cells produce

IL-17, -23, -22, -6 and TNF-α in the presence of TGF-β, IL-1β and -6, whereas Tregs appear in the

presence of TGF-β and release the immunosuppressive cytokines IL-10 and TGF-β. IL-17 is implicated in

the pro-duction of various inflammatory mediators such as TNF-α, PGE2, IL-6 and -1β, mediating bone

resorption by osteoclasts activation (34,36). Tregs and Th17 cells are present in periodontal tissue with an

increased expression of Foxp3 and IL-17, suggesting their crucial role in the immunoregulation of

periodontitis (33,34,37). It has also been shown a plasticity between Th17 and Treg cell subsets which are

present in the same tissues, and especially in periodontitis lesions (37). However, the role of the

association between the Treg/Th17andTh1/Th2, and their cross-talk in the pathogenesis of periodontitis it

still remains unclear.

The inflammatory reaction involves in addition to recruited inflammatory cells, blood vessels, and their

endothelial cells and smooth muscle cells that are come in contact with the recruited inflammatory cells.

Gingival fibroblasts, resident cells of the connective tissue, produce inflammatory mediators, such as

cytokines, chemokines, proteolytic enzymes and PGs which are involved in the inflammatory response

and contribute to disease persistence (38-44). Periodontal ligament fibroblasts, which are located between

the tooth and the alveolar bone, are also implicated in the inflammatory reaction and produce

inflammatory mediators such as PGs, proteolytic enzymes and factors which affect bone resorption.

During the inflammatory process, proinflammatory mediators are released and in turn affect various cell

types and promote the inflammatory pathway (45-47).

Cytokines and Chemokines

Various pro-inflammatory cytokines such as IL-1, -6, -12, -17, -18, -21, TNF-α and IFN-γ and

chemokines such as IL-8, Monocyte Chemoattractant Protein-1 (MCP-1), Macrophage Inflammatory

Protein-1α (MIP1α), and chemokine (C-C motif) ligand 5 (CCL5) have been identified in the Gingival

Crevicular Fluid (GCF), and in gingival tissue from patients with periodontitis and are implicated in its

pathogenesis (48).

TNF-α is released from mast cells in response to bacterial antigens and has a crucial role at an early

phase of the inflammatory reaction. Periodontal tissue cells that also produce TNF-α and IL-1 are PMN

cells, monocytes/macrophages, epithelial and endothelial cells, fibroblasts, and osteoblasts (48). Those

inflammatory cytokines are increased in GCF and gingival tissue with periodontitis (49-51). Their role in

periodontitis has been proven as after periodontal treatment their levels were reduced (52, 53).

Experimental studies have shown that soluble receptors of IL-1 and TNF-α inhibit the progress of

periodontitis in a primate model (54,55). During the inflammatory reaction those cytokines are implicated



in the induction of other inflammatory mediators, such as IL-6, -8, Matrix Metalloproteinases (MMPs)

and PGE2, whereas are also involved in bone resorption (56-60).

IL-6 is a pro-inflammatory cytokine, released by lymphocytes, monocytes, epithelial cells, and

fibroblasts in response to bacterial LPS, IL-1 and TNF-α and is implicated in the formation of osteoclasts

in vitro (57,61). Periodontitis patients’ GCF and gingival tissue are characterized by increased levels of

IL-6, compared with healthy locations (62, 63). Similarly, after nonsurgical periodontal treatment IL-6

levels have been found to be decreased (64). Chemokines are cytokines implicated in inducing

chemotaxis in responsive cells. IL-8 is a chemokine released by various cells, such as epithelial and

endothelial cells, monocytes, lymphocytes, and fibroblasts, in response to IL-1, TNF-α and LPS and

recruits neutrophils and other leucocytes to the inflammation site (56, 65). In aggressive periodontitis

gingival tissues show increased levels of IL-8 expression, which especially are identified to areas with

high concentrations of PMN cells (66). Similarly, elevated levels of IL-8 have been found in GCF in

periodontitis sites compared with healthy ones, whereas its levels were decreased after periodontal

treatment (67).

The chemokine MCP-1 is produced by epithelial cells, fibroblasts, and endothelial cells, in response to

bacterial endotoxins such as LPS or inflammatory mediators (57, 68), whereas in periodontitis MCP-1

and MIP-1α attract neutrophils and other leucocytes to the inflammation site (56,65). In periodontitis

pathogenesis is also involved the chemokine (C-C motif) ligand 5(CCL5) as they have been found

elevated levels in gingival biopsies and/or GCF, whereas after periodontal treatment were identified

decreased levels of CCL5 and other chemokines (49,53,69-73).

IL-1a, -1b, -12 (p40), -17, -18, -21, IFN-γ and TNF-α cytokines have been found to be increased in GCF

in periodontitis patients(49,52,53, 62,69-71,73-79). Similarly, chemokines such as MCP-1, MIP1a, and

CCL5 were also increased in periodontitis patients (53,70,74).

Interleukin-6 Expression and Gene Polymorphism

Bacterial invasion and environmental factors are implicated in initiation and modulation of PD

progression, however, evidence supports that genes have an important role in the predisposition to and

progression of periodontitis (80,81).

Cytokines and oral pathogens play central roles in the inflammatory process associated with the etiology

of periodontitis (82-84). Polymorphisms in the regulatory regions of the cytokine genes may change

cytokine expression. The cytokine gene polymorphism and expression could be contribute to the

identification of genetic factors that play a significant role in the periodontitis etiology and define the

susceptibility of individuals with respect to PD and clinical outcomes (85).

Based on previous reports it seems that IL-6 is implicated in the periodontitis pathogenesis (23,86). The

development of periodontitis is characterized by biological events that could be media-ted by the binding

of IL-6 and its receptor (IL-6R), including immunocyte activation, angiogene-sis, hematopoiesis, and



osteoclast differentiation (87). IL-6 levels are elevated in periodontitis patients (88,89) and decreased after

successful periodontal therapy (90,91), whereas in those patients IL-6 has been identified in serum, GCF,

and salivary, condition that proposes a modified production of IL-6 (92,93). IL-6 release has been

associated with the persistence of oral inflammation and tissue destruction caused by proteases,

osteoclasts, and methylation alterations (94-97), whereas increased levels of IL-6 expression is positively

correlated with attachment loss (98). IL-6 is also a potent stimulator of osteoclast differentiation and bone

resorption (99,100), whereas also regulates the expressionof cytokines such as IL-1, -10, and TNF-α

(101,102).

As already mentioned genetic factors may predispose to periodontitis (80,81). Thus, several studies have

been carried out to research whether IL-6 gene polymorphisms predispose to periodontitis. However, the

results regarding the possible associations between these polymorphisms and clinical forms of

periodontitis are conflicting.

Clinical studies indicated that IL-6 plays a crucial role in the inflammatory response to Gram-negative

bacteria (103) by affecting the constitution of the subgingival microbiota and increasing the susceptibility

to colonization with periopathogens bacteria, and in general is induced inresponse to several

inflammatory stimuli (104-107).

The simple nucleotide polymorphism (SNP) of the IL-6 promoter gene may affect the production and

expression of that cytokine, and consequently, this change in serum levels may result in a relevant

biological response (108).

Previous studies have reported an association of the IL-6-174G/C polymorphism and periodonti-tis and

suggested that IL-6 may be considered an important marker for its pathogenesis (4,109-112). Nibali et al.

(25) suggested a positive association between IL-6 -174 G/G genotype and the presence of A.

actinomycetemcomitans and Capnocytophaga sputigena in subgingival plaque. Similarly, Shao et al.

(113) in a systematic review and meta-analysis demonstrated that IL-6 G/G genotype could not modify

the risk of CP, but increased the risk of aggressive periodontitis. An increased expression of IL-6 and IL-6

-174G/C polymorphism was found to be associated with PD severity in Brazilian individuals (98),

whereas in another study was found that IL-6 -174 G/G genotypes and G allele seems to be associated

with aggressive periodontitis (114) and the extend of it (115). Trindade et al. (26) reported associations

between cytokine gene polymorphisms and periodontitis in distinct populations. The effect of that

polymorphism on the susceptibility of CP has been studied by multiple researchers and has been found

positive associations (110,116-121). The IL-6 -572 C/G polymorphism has also been studied in the

context of susceptibility to periodontitis. However, compared with C allele carriers (genotypes GC and

CC), the GG genotype significantly increased the risk of CP, suggesting that the -572 G allele is

associated with the pathogenesis of CP under the compliant genetic model (122-125). It has also been

shown that the same polymorphism was associated with the pathogenesis of periodontitis, as it

predisposes to either CP or aggressive periodontitis (113).



Polymorphisms in the regulatory regions of genes may alter the expression of cytokines revealing an

important role of genetic predictors of disease susceptibility and clinical measures (126). More

specifically, IL-6 -572 G/C polymorphisms have been associated with an increased protein expression

and inflammatory response (127).

Besides the IL-6 -174 G/C and -572 C/G polymorphisms, the -6331 T/C polymorphism in the promoter

region of the gene could also alter the transcriptional activity of IL-6. It is suggested that IL-6 -6331 T/C

polymorphism is implicated in the pathogenesis of periodontitis, but that association with risk of

periodontitis requires to be confirmed in other ethnics (128).

A study by Nibali et al. (129) supported the hypothesis of a link between IL-6 genetic factors and

aggressive periodontitis and highlights the importance of two IL-6 polymorphisms (-1363 and –1480) in

modulating disease phenotype and susceptibility. Another similar study (125) suggested the hypothesis

that IL-6 polymorphisms and haplotypes are moderately associated with periodontitis, possibly acting

through influencing tissue levels of IL-6.

On the contrary, some reports have shown no association between the polymorphism IL-6 -174 G/C and

PD. Fan et al. (130) observed a very low prevalence of the C allele and found no significant difference in

the genotypes distribution for the IL-6-174G/C polymorphism in the analysis of groups with PD and

coronary artery disease. Similarly, Holla et al. (122) found no significant differences between patients

with periodontitis and healthy controls regarding the genotype or allele frequencies between both groups

for IL-6 -174 G/C and-597 G/A polymorphisms. Another study conducted by Wohlfahrt et al. (131) also

revealed no association between IL-6 -174G/C polymorphism and other polymorphisms in CTLA-4,

DEFB1, ICAM-1, FasL, ICOS, CCR5, OPG, and OPN genes in individuals with PD. The same study

showed no significant association between this polymorphism and CP, finding that was in accordance

with the results of a previous analysis (132). Loo et al. (133) showed no association between genetic

polymorphisms in IL-6,-1b and IFN-γ genes and PD however, in the same study, associations with

polymorphisms in IL-1, TNF-α, IL-4 and -10 genes were described. Ianni et al. (134) found no

association, whereas in another report (130) was found that IL-6 -572C/G polymorphism did not correlate

with CP susceptibility, but might be a potential risk factor for Coronary Heart Disease in a Chinese popu-

lation. In addition, Holla et al.(122) suggested that the -572 G/C polymorphism of the IL-6 gene may be

one of the protective factors associated with lower susceptibility to chronic periodontitis.It was also

observed that the IL-6-373 A9T11 allele was associated with a reduced susceptibility to CP among

Japanese individuals and decreased IL-6 serum levels (124).

It is clear that the prevalence of IL-6 polymorphism varies in different samples and populations, and it

might also vary the association with susceptibility to periodontitis. That observation would lead to

discrepancies and contradictory results in genetic polymorphism studies carried out on periodontitis

patients of different ethnicities and various genetic backgrounds. Except from racial and genetic

differences, other differences could be attributed to possible confounders such as clinical diagnosis

criteria, environmental variables, biologic plausibility, and significant heterogeneity among the studies

reviewed, penetrance and logic of association studies (135).



References

1. Albandar JM, Rams TE. Global epidemiology of periodontal diseases: an overview. Periodontol 2000

2002;29:7-10.

2. Hirschfeld L, Wasserman B. A long-term survey of tooth loss in 600 treated periodontal patients. J

Periodontol 1978;49:225-237.

3. McGuire MK, Nunn ME. Prognosis versus actual outcome. III. The effectiveness of clinical

parameters in accurately predicting tooth survival. J Periodontol 1996;67:666-674.

4. Chambrone LA, Chambrone L. Tooth loss in well-maintained patients with chronic periodontitis

during long-term supportive therapy in Brazil. J Clin Periodontol 2006;33:759-764.

5. Faggion CM Jr, Petersilka G, Lange DE, et al. Prognostic model for tooth survival in patients treated

for periodontitis. J Clin Periodontol 2007;34:226-231.

6. Matuliene G, Pjetursson BE, Salvi GE, et al. Influence of residual pockets on progression of

periodontitis and tooth loss: results after 11years of maintenance. J Clin Periodontol 2008;35:685-695.

7. Suzuki N, Yoneda M, Hirofuji T. Mixed red-complex bacterial infection in periodontitis. Int J Dent

2013; 1-6: ID 587279.

8. Mo S, You M, Su YS, et al. Multilocus sequence analysis of Treponema denticola strains of diverse

origin. BMC Microbiol 2013;13:24.

9. Offenbacher S. Periodontal diseases: pathogenesis. Ann Periodontol 1996;1:821-788.

10. Hajishengallis G, Lamont RJ. Beyond the red complex and into more complexity: the polymicrobial

synergy and dysbiosis (PSD) model of periodontal disease etiology. Mol Oral Microbiol 2012;27:409-

419.

11. Costa AM, Guimaraes MCM, de Souza ER, et al. Interleukin-6(G-174C) and tumour necrosis factor-

alpha (G-308A) gene polymorphisms in geriatric patients with chronic periodontitis. Gerodontology

2010;27:70-75.

12. Archana PM, Arif Salman A, Kumar TSS, et al. Association between interleukin-1gene

polymorphism and severity of chronic periodontitis in a south Indian population group. J Ind Soc

Periodontol 2012;16:174-178.

13. Oppermann RV, Weidlich P, Musskopf ML. Periodontal disease and systemic complications. Braz

Oral Res 2012;26:39-47.

14. Chaffee BW, Weston SJ. Association between chronic periodontal disease and obesity: a systematic

review and metaanalysis. J Periodontol 2010;81:1708-1724.

15. Stabholz A, Soskolne WA, Shapira L. Genetic and environmental risk factors for chronic periodontitis

and aggressive periodontitis. Periodontol 2000 2010;53:138-53.



16. D'Aiuto F, Graziani F, Tete S, et al. Periodontitis: from local infection to systemic diseases. Int J

Immunopathol Pharmacol 2005;18S:1-11.

17. Kornman K.S. Mapping the pathogenesis of periodontitis: a new look. J Periodontol 2008;79:1560-

1568.

18. Salvi GE, Carollo-Bittel B, Lang NP. Effects of diabetes mellitus on periodontal and peri implant

conditions: update on associations and risks. J Clin Periodontol 2008;35:398-409.

19. Page RC, Offenbacher S, Schroeder HE, et al. Advances in the pathogenesis of periodontitis:

summary of developments, clinical implications and future directions. Periodontol 2000 1997;14:216-

248.

20. Yücel OO, Berker E, Gariboğlu S, et al. Interleukin-11, interleukin-1beta, interleukin-12 and the

pathogenesis of inflammatory periodontal diseases. J Clin Periodontol 2008 ;35:365-370.

21. Garlet GP, Trombone AP, Menezes R, et al. The use of chronic gingivitis as reference status increases

the power and odds of periodontitis genetic studies: a proposal based in the exposure concept and clearer

resistance and susceptibility phenotypes definition. J Clin Periodontol 2012; 39: 323-332.

22. Zhang J, Sun X, Xiao L, et al. Gene polymorphisms and periodontitis. Periodontol 2000 2011;

56:102-124.

23. Laine ML, Crielaard W, Loos BG. Genetic susceptibility to periodontitis. Periodontol 2000 2012;58:

37-68.

24. Kalburgi NB, Bhatia A, Bilichodmath S, et al. Interleukin-6 promoter polymorphism(-174 G/C) in

Indian patients with chronic periodontitis. J Oral Sci 2010;52:431-437.

25. Nibali L, Madden I, Chillida FF, et al. IL6-174 genotype associated with Aggregatibacter

actinomycetemcomitans in Indians. Oral Dis 2011;17:232-237.

26. Trindade SC, Olczak T, Gomes-Filho IS, et al. Porphyromonas gingivalis HmuY-induced production

of interleukin- 6 and il-6 polymorphism in chronic periodontitis. J Periodontol 2013;84:650-655.

27. Nibali L, Donos N, Farrell S, et al. Association between interleukin-6 -174 polymorphism and

Aggregatibacter actinomycetemcomitans in chronic periodontitis. J Periodontol 2010;81:1814-1819.

28. Page RC, Kornman KS. The pathogenesis of human periodontitis: an introduction. Periodontol 2000

1997;14:9-11.

29. Eke PI, Dye BA, Wei L, et al. Update on prevalence of periodontitis in adults in the United States:

NHANES 2009 to 2012. J Periodontol 2015;86:611-622.

30. Kassebaum NJ, Bernabe´ E, Dahiya M, et al. Global burden of severe periodontitis in1990- 2010: A

systematic review and meta-regression. J Dent Res 2014;93:1045-1053.

31. Graves D. Cytokines that promote periodontal tissue destruction. J Periodontol 2008;79:1585-1591.

32. Mahanonda R, Pichyangkul S. Toll-like receptors and their role in periodontal health and disease.

Periodontol 2000 2007;43:41-55.



33. Van Dyke TE, van Winkelhoff AJ. Infection and inflammatory mechanisms. J Clin Periodontol 2013;

40: S1-S7

34. Ohlrich EJ, Cullinan MP, Seymour GJ . The immunopathogenesis of periodontal disease. Aust Dent J

2009;54:S2-S10.

35. Page RC, Schroeder HE. Pathogenesis of inflammatory periodontal disease: a summary of current

work. Lab Invest 1976;34:235-249.

36. Lindberg TY, Båge T. Inflammatory mediators in the pathogenesis of periodontitis. Expert Rev Mol

Med 2013;15:e7.

37. Okui T, Aoki Y, Ito H, et al. The presence of IL-17 + /FOXP3+ double positive cells in

periodontitis. J Dent Res 2012;91:574-579.

38. Kornman KS, Page RC, Tonetti MS. The host response to the microbial challenge in periodontitis:

assembling the players. Periodontol 2000 1997;14:33-53.

39. Flavell SJ, Hou TZ, Lax S, et al. Fibroblasts as novel therapeutic targets in chronic inflammation. Br J

Pharmacol 2008;153:S241-S246.

40. Heath JK, Atkinson SJ, Hembry RM, et al. Bacterial antigens induce collagenase and prostaglandin

E2 synthesis in human gingival fibroblasts through a primary effect on circulating mononuclear cells.

Infect Immun 1987;55:2148-2154.

41. Meikle MC, Hembry RM, Holley J, et al. Immunolocalization of matrix metalloproteinases and

TIMP-1 (tissue inhibitor of metalloproteinases) in human gingival tissues from periodontitis patients. J

Periodontal Res 1994; 29, 118-126.

42. Reynolds JJ, Meikle MC. Mechanisms of connective tissue matrix destruction in periodontitis.

Periodontol 2000 1997;14: 144-157.

43. Bage T, Lindberg J, Lundeberg J, et al. Signal pathways JNK and NF kappa B, identified by global

gene expression profiling, are involved in regulation of TNF alpha-induced mPGES-1 and COX-2

expression in gingival fibroblasts. BMC Genomics 2010;11:241-200.

44. Domeij H, Modeer T, Yucel-Lindberg T. Matrix metalloproteinase-1 and tissue inhibitor of

metalloproteinase-1 production in human gingival fibroblasts: the role of protein kinase C. J Periodontal

Res 2004;39:308-314.

45. Nishikawa M, Yamaguchi Y, Yoshitake K, et al. Effects of TNF alpha and prostaglandin E2 on the

expression of MMPs in human periodontal ligament fibroblasts. J Periodontal Res 2002;37:167-176.

46. Noguchi K, Shitashige M, Ishikawa I. Involvement of cyclooxygenase-2 in interleukin-1 alpha

induced prostaglandin production by human periodontal ligament cells. J Periodontol 1999;70:902-908.

47. Hormdee D, Nagasawa T, Kiji M, et al. Protein kinase-A dependent osteoprotegerin production on

interleukin-1 stimulation in human gingival fibroblasts is distinct from periodontal ligament fibroblasts.

Clin Exp Immunol 2005;142:490-497.



48. Graves DT, Cochran D. The contribution of interleukin-1 and tumor necrosis factor to periodontal

tissue destruction. J Periodontol 2003;74:391-401.

49. Kurtis B, Tüter G, Serdar M, et al. Gingival crevicular fluid levels of monocyte chemoattractant

protein-1 and tumor necrosis factor-alpha in patients with chronic and aggressive periodontitis. J

Periodontol 2005;76:1849-1855.

50. Perozini C, Chibebe PCA, Pereira Leao MV, et al. Gingival crevicular fluid biochemical markers in

periodontal disease: a cross-sectional study. Quintessence Int 2010;41:877-883.

51. Stashenko P, Jandinski JJ, Fujiyoshi P, et al. Tissue levels of bone resorptive cytokines in periodontal

disease. J Periodontol 1991;62:504-509.

52. Holmlund A, Hanstrom L, Lerner UH. Bone resorbing activity and cytokine levels in gingival

crevicular fluid before and after treatment of periodontal disease. J Clin Periodontol 2004;31:475-482.

53. Gamonal J, Acevedo A, Bascones A, et al. Levels of interleukin-1 beta,-8, and -10 and RANTES in

gingival crevicular fluid and cell populations in adult periodontitis patients and the effect of periodontal

treatment. J Periodontol 2000;71:535-1545.

54. Assuma R, Oates T, Cochran D, et al. IL-1 and TNF antagonists inhibit the inflammatory response

and bone loss in experimental periodontitis. J Immunol 1998;160:403-409.

55. Delima AJ, Oates T, Assuma R, et al. Soluble antagonists to interleukin-1 (IL-1) and tumor necrosis

factor (TNF) inhibits loss of tissue attachment in experimental periodontitis. J Clin Periodontol 2001;28:

233-240.

56. Bascones A, Noronha S, Gómez M, et al. Tissue destruction in periodontitis: bacteria or cytokines

fault? Quintessence Int 2005;36:299-306.

57. Madianos PN, Bobetsis YA, Kinane DF. Generation of inflammatory stimuli: how bacteria set up

inflammatory responses in the gingiva. J Clin Periodontol 2005;32:57-71.

58. Weber A, Wasiliew P, Kracht M. Interleukin-1 (IL-1) pathway. Sci Signal 2010;19: 3:cm1

59. Kwan Tat S, Padrines, Théoleyre S, et al. IL-6, RANKL, TNF-alpha / IL-1: interrelations in bone

resorption pathophysiology. Cytokine Growth Factor Rev 2004;15:49-60.

60. Yucel-Lindberg T, Nilsson S, Modeer T. Signal transduction pathways involved in the synergistic

stimulation of prostaglandin production by interleukin-1beta and tumor necrosis factor alpha in human

gingival fibroblasts. J Dent Res 1999;78:61-68.

61. Deo V, Bhongade ML. Pathogenesis of periodontitis: role of cytokines in host response. Dent Today

2010; 29, 60-62, 64–66;quiz 68–69.

62. Kurtis B, Develioğlu H, Taner IL, et al. IL-6 levels in gingival crevicular fluid (GCF) from patients

with noninsulin dependent diabetes mellitus (NIDDM), adult periodontitis and healthy subjects. J Oral Sci

1999;41:163-167.

63. Prabhu A, Michalowicz BS, Mathur A. Detection of local and systemic cytokines in adult

periodontitis. J Periodontol 1996;67:515-522.



64. Marcaccini AM, Meschiari CA, Sorgi CA, et al. Circulating interleukin-6and high-sensitivity C-

reactive protein decrease after periodontal therapy in otherwise healthy subjects. J Periodontol 2009;80:

594-602.

65. Huang GT, Haake SK, Park NH. Gingival epithelial cells increase interleukin-8 secretion in response

to Actinobacillus actinomycetemcomitans challenge. J Periodontol 1998;69:1105- 1110.

66. Liu RK, Cao CF, Meng HX, et al. Polymorphonuclear neutrophils and their mediators in gingival

tissues fromgeneralized aggressive periodontitis. J Periodontol 2001;72:1545-1553.

67. Gamonal J, Acevedo A, Bascones A, et al. Characterization of cellular infiltrate, detection of

chemokine receptor CCR5 and interleukin-8 and RANTES chemokines in adult periodontitis. J

Periodontal Res 2001;36:194-203.

68. Preshaw PM, Taylor JJ. How has research into cytokine interactions and their role in driving immune

responses impacted our understanding of periodontitis? J Clin Periodontol 2011;38:60-84.

69. Thunell DH, Tymkiw KD, Johnson GK, et al. A multiplex immunoassay demonstrates reductions in

gingival crevicular fluid cytokines following initial periodontal therapy. J Periodontal Res 2010;45:148-

152.

70. Tymkiw KD, Thunell DH, Johnson GK, et al. Influence of smoking on gingival crevicular fluid

cytokines in severe chronic periodontitis. J Clin Periodontol 2011;38:219-228.

71. Pradeep AR, Daisy H, Hadge P, et al. Correlation of gingival crevicular fluid interleukin-18 and

monocyte chemoattractant protein-1 levels in periodontal health and disease. J Periodontol 2009;80:

1454-1461.

72. Garlet GP, Martins Jr W, Ferreira BR, et al. Patterns of chemokines and chemokine receptors

expression in different forms of human periodontal disease. J Periodontal Res 2003;38:10- 217.

73. Rescala B, Rosalem Jr W, Teles RP,et al. Immunologic and microbiologic profiles of chronic and

aggressive periodontitis subjects. J Periodontol 2010;81:1308-1316.

74. Giannopoulou C, Kamma JJ, Mombelli A. Effect of inflammation, smoking and stress on gingival

crevicular fluid cytokine level. J Clin Periodontol 2003;30:145-153.

75. Ertugrul AS, Sahin H, Dikilitas A, et al. Comparison of CCL28, inter leukin-8, interleukin 1beta and

tumor necrosis factor-alpha in subjects with gingivitis, chronic periodontitis and generalized aggressive

periodontitis. J Periodontal Res 2013;48:44-51.

76. Fujita Y, Ito H, Sekino S, et al. Correlations between pentraxin 3 or cytokine levels in gingival

crevicular fluid and clinical parameters of chronic periodontitis. Odontology 2012;100:215-221.

77. Vernal R, Dutzan N, Chaparro A, et al. Levels of interleukin-17 in gingival crevicular fluid and in

supernatants of cellular cultures of gingival tissue from patients with chronic periodontitis. J Clin

Periodontol 2005;32:383-389.

78. Dutzan N, Rivas C, García-Sesnich J, et al. Levels of interleukin-21in patients with untreated chronic




79. Dutzan N, Vernal R, Hernandez M, et al. Levels of interferon-gamma and transcription factor T-bet in

progressive periodontal lesions in patients with chronic periodontitis. J Periodontol 2009;80:290-296.

80. Kinane DF, Hart TC. Genes and gene polymorphisms associated with periodontal disease. Crit Rev

Oral Biol Med 2003;14:430-349.

81. Stabholz A, Soskolne WA, Shapira L. Genetic and environmental risk factors for chronic periodontitis

and aggressive periodontitis. Periodontol 2000, 2010;53:138-153.

82. Taylor JJ, Preshaw PM, Donaldson PT. Cytokine gene polymorphism and immunoregulation in

periodontal disease. Periodontol 2000, 2004; 35: 158-182.

83. Wu YM, Yan J, Chen LL, et al. Association between infection of different strains of Porphyromonas

gingivalis and Actinobacillus actinomycetemcomitans in subgingival plaque and clinical parameters in

chronic periodontitis. J Zhejiang Univ Sci B 2007;8:121-131.

84. He XS, Shi WY. Oral microbiology: past, present and future. Int J Oral Sci 2009;1:47-58.

85. Gu W, Du DY, Huang J, et al. Identification of interleukin-6 promoter polymorphisms in the Chinese

Han population and their functional significance. Crit Care Med 2008;36:1437- 1443.

86. Matsui S, Ogata Y. Effects of miR-223 on expression of IL-1beta and IL-6 in human gingival

fibroblasts. J Oral Sci 2016; 58: 101-108.

87. Nibali L, Fedele S, D’Aiuto F, et al. Interleukin-6 in oral diseases: a review. Oral Dis 2012;18:236-

243.

88. Loos BG. Systemic markers of inflammation in periodontitis. J Periodontol 2005;76:2106-2115.

89. Loos BG, Craandijk J, Hoek FJ, et al. Elevation of systemic markers related to cardiovascular diseases

in the peripheral blood of periodontitis patients. J Periodontol 2000;71:1528-1534.

90. D'Aiuto F, Parkar M, Andreou G, et al. Periodontitis and systemic inflammation: control of the local

infection is associated with a reduction in serum inflammatory markers. J Dent Res 2004; 83: 156-160.

91. D' Aiuto F, Parkar M, Brett PM, et al. Gene polymorphisms in pro-inflammatory cytokines are

associated with systemic inflammation in patients with severe periodontal infections. Cytokine 2004;28:

29-34.

92. Costa PP, Trevisan GL, Macedo GO, et al. Salivary interleukin-6, matrix metalloproteinase- 8, and

osteoprotegerin in patients with periodontitis and diabetes. J Periodontol 2010;81:384-391.

93. Shimada Y, Komatsu Y, Ikezawa-Suzuki I, et al. The effect of periodontal treatment on serum leptin,

interleukin-6, and C-reactive protein. J Periodontol 2010;81:1118-1123.

94. McCauley LK, Nohutcu RM. Mediators of periodontal osseous destruction and remodeling: principles

and implications for diagnosis and therapy. J Periodontol 2001;73:1377-1391.

95. Belibasakis GN, Johansson A, Wang Y, et al. Cytokine responses of human gingival fibroblasts to

Actinobacillus actinomycetemcomitans cytolethal distending toxin. Cytokine 2005;30:56-63.



96. Gasche JA, Hoffmann J, Boland CR, et al. Interleukin-6 promotes tumorigenesis by altering DNA

methylation in oral cancer cells. Int J Cancer 2011;129:1053-1063.

97. Matsushima K, Ohbayashi E, Takeuchi H, et al. Stimulation of interleukin-6 production in human

dental pulp cells by peptidoglycans from lactobacillus casei. J Endodont 1998;24:252-255.

98. Moreira PR, Lima PM, Sathler KO, et al. Interleukin-6 expression and gene polymorphism are

associated with severity of periodontal disease in a sample of Brazilian individuals. Clin Exp Immunol

2007;148:119-126.

99. Gemmell E, Marshall RI, Seymour GJ. Cytokines and prostaglandins in immune homeostasis and

tissue destruction in periodontal disease. Periodontol 2000 1997;14:112-143.

100. Hughes FJ, Turner W, Belibasakis G, et al. Effects of growth factors and cytokines on osteoblast

differentiation. Periodontol 2000 2006;41:48-72.

101. Opal SM, DePalo VA. Anti-inflammatory cytokines. Chest 2000;117:1162-1172.

102. Woods A, Brull DJ, Humphries S, et al. Genetics of inflammation and risk of coronary artery

disease: the central role of interleukin-6. Eur Heart J 2000;21:1574-1583.

103. Dalrymple SA, Slattery R, Aud DM, et al. Interleukin-6 is required for aprotective immune response

to systemic Escherichia coli infection. Infect Immunol 1996;64:3231-3235.

104. Terry CF, Loukaci V, Green FR. Cooperative influence of genetic polymorphisms on interleukin 6

transcriptional regulation. J Biol Chem 2000; 275:18138-18144.

105. Cooke GS, Hill AV. Genetics of susceptibility to human infectious disease. Nat Rev Genet 2001; 2:

967-977.

106. Coats SR, To TT, Jain S, et al. Porphyromonas gingivalis resistance to polymyxin B is determined

by the lipid A 4′-phosphatase, PGN_0524. Int J Oral Sci 2009;1:126-135.

107. Ishihara Y, Nishihara T, Kuroyanagi T, et al. Gingival crevicular interleukin-1 and interleukin-1

receptor antagonist levels in periodontally healthy and diseased sites. J Periodontal Res 1997;32:524-529.

108. Mao L, Geng GY, Han WJ, et al. Interleukin-6 (IL-6) -174G/C genomic polymorphism contribution

to the risk of coronary artery disease in a Chinese population. Genet Mol Res 2016;15.

109. Scapoli L, Girardi A, Palmieri A, et al. IL6 and IL10 are genetic susceptibility factors of periodontal

disease. Den Res J 2012;9:197-201.

110. Brett PM, Zygogianni P, Grifths GS, et al. Functional gene polymorphisms in aggressive and

chronic periodontitis. J Dent Res 2005;84:1149-1153.

111. Teixeira FG, Samir Andrade Mendonça SA, Oliveira KM, et al. Interleukin-6 c.-174G>C

Polymorphism and Periodontitis in a Brazilian Population. Mol Biol Int 2014;8:1-8.

112. Raunio T, Nixdorf M, Knuuttila M, et al. The extent of periodontal disease and the IL-6- 174

genotype as determinants of serum IL-6 level. J Clin Periodontol 2007;34:1025-1030.



113. Shao M-Y, Huang P, Cheng R, et al. Interleukin-6 polymorphisms modify the risk of periodontitis: a

systematic review and meta-analysis. J Zhejiang Univ Sci B 2009;10:920-927.

114. Hülya Toker, Emine Pirim Görgün, Ertan Mahir Korkmaz. Analysis of IL-6, IL-10 and NF- κB Gene

Polymorphisms in Aggressive and Chronic Periodontitis. Cent Eur J Public Health 2017;25:157-162.

115. Tervonen T, Raunio T, Knuuttila M, et al. Polymorphisms in the CD14 and IL-6 genes associated

with periodontal disease. J Clin Periodontol 2007;34:377-83.

116. Junfei Zhu, Bin Guo, Min Fu, et al. Interleukin-6-174G/C Polymorphism Contributes to

Periodontitis Susceptibility: An Updated Meta-Analysis of 21 Case-Control. Dis Markers 2016; ID

9612421.

117. Trevilatto PC, Scarel-Caminaga RM, de Brito RB Jr, et al. Polymorphism at position -174 of IL-6

gene is associated with susceptibility to chronic periodontitis in a Caucasian Brazilian population. J Clin

Periodontol 2003;30:438-442.

118. Casado PL, Villas-Boas R, de Mello W, et al. Peri-implant disease and chronic periodontitis: is

interleukin-6 gene promoter polymorphism the common risk factor in a Brazilian population? Int J Oral

Maxillofac Implants 2013;28:35-43.

119. Dosseva-Panova V, Mlachkova A, Popova C, et al. Evaluation of interleukin-6, lympho toxin-α and

TNF-α gene polymorphisms in chronic periodontitis. J IMAB-Ann Proc 2015;21:868-875.

120. Gabriela Teixeira F, Mendonca SA, Menezes Oliveira K, et al.

Interleukin-6 c.-174G > C

polymorphism and periodontitis in a Brazilian population. Mol Biol Int 2014; ID 490308.

121. Babel N, Cherepnev G, Babel D, et al. Analysis of tumor necrosis factor-α transforming growth

factor-β interleukin-10, IL-6, and interferon-gamma gene polymorphisms in patients with chronic


122. Holla LI, Fassmann A, Stejskalova A, et al. Analysis of the inter leukin-6 gene promoter

polymorphisms in Czech patients with chronic periodontitis. J Periodontol 2004;75:30-36.

123. Holla LI, Fassmann A, Augustin P, et al. The association of interleukin-4 haplotypes with chronic

periodontitis in a Czech population. J Periodontol 2008;79:1927-1933.

124. Komatsu Y, Tai H, Galicia JC, et al. Interleukin-6 (IL-6) -373 A9T11 allele is associated with

reduced susceptibility to chronic periodontitis in Japanese subjects and decreased serum IL-6 level.

Tissue Antigens 2005;65:110-114.

125. Nibali L, D'Aiuto F, Donos N, et al. Association between periodontitis and common variants in the

promoter of the interleukin-6 gene. Cytokine 2009;45:50-54.

126. Lamster IB, Hartley LJ, Vogel RI. Development of a biochemical profile for gingival crevicular

fluid. Methodological considerations and evaluation of collagen-degrading and ground substance-

degrading enzyme activity during experimental gingivitis. J Periodontol 1985;56:13-21.

127. Fonseca JE, Santos MJ, Canhão H, et al. Interleukin-6 as a key player in systemic inflammation and

joint destruction. Autoimmun Rev 2009;8:538-542.

https://pubmed.ncbi.nlm.nih.gov/25548674/#affiliation-4



128. Smith AJ, D'Aiuto F, Palmen J, et al. Association of serum interleukin-6 concentration with a

functional IL6 -6331T>C polymorphism. Clin Chem 2008;54:841-850.

129. Nibali L, Griffiths GS, Donos N, et al. Association between interleukin-6 promoter haplo types and

aggressive periodontitis. J Clin Periodontol 2008;35:193-198.

130. Fan WH, Liu DL, Xiao LM, et al. Coronary heart disease and chronic periodontitis: is polymorphism

of interleukin-6 gene the common risk factor in a Chinese population? Oral Dis 2001;17:270-276.

131. Wohlfahrt JC, Wu T, Hodges JS, et al. No association between selected candidate gene

polymorphismsand severe chronic periodontitis. J Periodontol 2006;77:426-436.

132. Nikolopoulos GK, Dimou NL, Hamodrakas SJ, et al. Cytokine gene polymorphisms in periodontal

disease: a meta-analysis of 53 studies including 4178 cases and 4590 controls. J Clin Periodontol 2008;

35:754-767.

133. Loo WTY, Fan C-B, Bai L-J, et al. Gene polymorphism and protein of human pro and anti-

inflammatory cytokines in Chinese healthy subjects and chronic periodontitis patients. J Transl Med

2012;10:S8.

134. Ianni M, Bruzzesi G, Pugliese D, et al. Variations in inflammatory genes are associated with

periodontitis. Immun Ageing 2013;10:39.

135. Kinane DF, Hart TC. Genes and gene polymorphisms associated with periodontal disease. Crit Rev

Oral Biol Med. 2003;14:430-449.

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The Role of Inflammatory Cytokines and Interleukin-6 ... · Chronic Periodontitis (CP) is a chronic inﬂammatory pathological condition caused by the interaction between microorganisms