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Interleukins in periodontal health and disease.

INTRODUCTION

Periodontal diseases, a series of infections of the periodontal tissues which eventually can lead to loss of teeth, are form of aberrant inflammation. (1) The release of inflammatory mediators and cytokines as local host response to the periodontopathic bacteria appears to play crucial roles in the pathogenesis of periodontal diseases. (1) Many biological events are strictly regulated by cell-cell interactions, which may be either cognate (adhesive) interactions, achieved by membrane-bound cell-surface molecules; or cytokine-mediated interactions. Cytokines are small soluble proteins produced by a cell that alter the behavior or properties of another cell locally or systemically in an autocrine or paracrine manner. They are pleiotropic molecules and most of them are multifunctional. Cytokines are involved in extensive networks that involve synergistic as well as antagonistic interactions and exhibit both negative and positive regulatory effects on various target cells. (1) These play an important role in numerous biological activities including proliferation, development, differentiation, homoeostasis, regeneration, repair and inflammation. (2)

Thus, the investigation of interleukins responses to periodontal diseases is at the forefront of the translational research agenda in oral science. This review summarizes interleukin expression in periodontal tissues and its importance in tissue homeostasis and, in particular, in the pathogenesis of periodontal diseases.

Interleukins are a large group of immunomodulatory proteins that elicit a wide variety of responses in cells and tissues. Interleukins initiate a response by binding to high-affinity receptors located on the surface of cells; Interleukins function in a paracrine or autocrine fashion, rather than as an endocrine signal, which is more common with steroidal and amino acid-derived hormones. The response of a particular cell to these cytokines depends on the ligands involved, specific receptors expressed on the cell surface and the particular signalling cascades that are activated. ILs modulate growth, differentiation and activation during an immune response. This distinguishes them from chemokines--the main function of which is to direct immune cells to the site of inflammation via chemotaxis--and interferons (IFNs), which predominantly mediate cellular response to viral infection.

The Nomenclature of Interleukins

The term interleukin derives from (inter-) "as a means of communication", and (-leukin) "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes". The term interleukin was coined by Dr. Paetkau, University of Victoria. Being non-structural proteins, biological properties were and still are the gold standards for defining a cytokine. The interleukin nomenclature was invented to deal with the issue of multiple biological properties of cytokines. At the time of naming these molecules with an interleukin number, primary amino acid sequences of the active molecules were not known. But the nomenclature did nothing to resolve the broader issue of multiple biological properties ascribed to a single molecule. (3)

Classification of Cytokines

The local host response to the oral pathogens capable of causing periodontal disease includes the recruitment of leukocytes and the subsequent release of inflammatory mediators and cytokines, which appear to play crucial roles in the pathogenesis of periodontal diseases. (2, 4) Cytokines are generally classified by their ability promote or inhibit inflammatory responses. (5) The classification of cytokines is shown in. An inflammatory cytokine is defined as a cytokine which is induced during the course of an inflammatory response and is closely associated with its onset and/or progression. Thus far, IL-la, IL- 113, IL-6, 1L-8, and TNI-7-7 are generally classified as inflammatory cytokines. (5)

INTERLEUKINS INVOLVED IN INFLAMMATION

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CYTOKINES V/S CHEMOKINES

The term chemokines, a short form of 'chemotactic cytokines', was coined in 1992. All the 50 or so human chemokines that were discovered over the years have chemo-tactic activity. They constitute a large family of mediators of inflammation and immunity with similarity to cytokines, but also some clear differences. Like cytokines the chemokines are secretory proteins produced by leucocytes and tissues cells either constitutively or after induction, and exert their effects locally in paracrine or autocrine fashion.

Interleukin Expression in Gingival and Periodontal Health

Tissue homeostasis represents a delicate balance between anabolic and catabolic activities. The regulations of migration, proliferation and differentiation of resident cells and of the production of tissue matrix in a healthy state are major aspects of periodontal tissue homeostasis. There is abundant evidence that myriad cytokines are involved in the maintenance of periodontal tissue turnover or integrity. (2)

Epithelium

The epithelium plays an active role in the pathogenesis of inflammation The gingival epithelium consists of keratinocytes, Langerhans cells, T-cells, Merckel cells and melanocytes. (3) Keratinocytes, when challenged, with bacterial infection, express a large variety of cytokines and growth factors including interleukin-1 alpha (IL-1a), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-a) and platelet-derived growth factor(PDGF). However, it is unknown whether cytokines and growth factors expressed by gingival epithelium are released in amounts sufficient to regulate remodeling in connective tissues of the periodontium. (6)

Connective tissue (fibroblast)

The dominant cell types are fibroblasts in the gingiva and fibroblast-like cells (called periodontal ligament cells) in the periodontal ligament. These cells express a variety of membrane and intracellular receptors, making the cells sensitive to regulate by many physiological and pathological, paracrine and endocrine signaling molecules. (6) During inflammation, resident gingival fibroblasts are triggered by cytokines (released by macrophages) to enhance their synthesis of cytokines. IL-1 is the most potent regulator of extracellular matrix turnover by enhancing the expression of several matrix metalloproteinase. Interleukin-1 beta (IL-1b) and TNF-a stimulate the expression and release of interleukin-6 (IL-6), leukemia inhibitory factor and Interleukin-11 (IL-11) in human gingival fibroblasts. (8)

Interleukins play a major role in initiation and progression of inflammatory process. However, a variety of different interleukins are involved in acute inflammation. These are summarized in Table 2

Interleukins Involved in Chronic Inflammation

Chronic inflammation may develop following acute inflammation and may last for weeks or months, and in some instances for years.

The detailed description of interleukins involved in Chronic Inflammation is shown in Table 4.

EVIDENCE

A variety of studies have been conducted to elicit the function and structure of interleukins.These are summarized in Table 5.

Role of Interleukins in Pathogensis of Gingival Diseases

Gingival Enlargement (9)

Phenytoin drug is used for treatment of epilepsy. It reacts with phenotypically distinct subpopulation of gingival fibroblast and cause an increase in protein synthesis and cell proliferation rate. IL1 and 6 found in higher levels in gingival crevicular fluid in phenytoin induced gingival over growth. It is suggested that this interleukin play indirect role in complex mechanism of phenytoin induced gingival over growth. (9)

Role of Interleukins in Pathogenesis of Periodontal Diseases

IL- I is known to stimulate the proliferation of keratinocytes, fibroblasts, and endothelial cells in an autocrine or paracrine fashion, and to enhance fibroblast synthesis of type I procollagen, collagenase, hyaluronate, fibronectin, and prostaglandin E2. IL-I is, therefore, a critical component in the homeostasis of periodontal tissues. (6, 10) These mediators may be responsible for effecting connective tissue destruction, leading to loss of attachment. IL-1a, IL 1b, and TNF-a stimulate bone resorption and inhibit bone formation. It synergizes the bone-resorptive actions of TNF-alpha, induces the production of matrix metalloproteinase (MMPs), gives rise to an elevated level of procollagenase in both gingival fibroblasts and periodontal ligament (PDL) cells. (6) No significant change in tissue inhibitors of metalloproteinase (TIMP) synthesis and mRNA was observed after treatment of gingival fibroblasts and PDL cells with IL- I b. In addition, IL-1 stimulates plasminogen activator in gingival fibroblasts, resulting in the generation of plasmin which is a putative, naturally occurring, activator of several matrix metalloproteinase.

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Interleukin-1, diacyllipopeptide and lipopolysaccharide are recognized by interleukin-1 receptor (IL- 1 R), a complex of TLR2 and TLR6, and TLR4, respectively. CD14 is a membrane-anchored glycoprotein that aids the binding of lipopolysaccharide and TLR4. IL-1R and the TLRs possess a common TIR domain. Through their TIR domains, IL-1R and the TLRs activate MyD88 as a common signaling molecule. TRAF6 is a signaling molecule downstream of MyD88. Thus, interleukin1 and diacyllipopeptide activate the MyD8S / TRAF6 pathway to induce biological responses. In contrast, TLR4 has two signaling pathways: the MyD88 / TRAF6 pathway and the TRAM / TRIF pathway. The TRAM / TRIF pathway plays an essential role in interferon-b production. In macrophages, both the MyD88/TRAF6 and TRAM TRIF pathways are required for lipopolysaccharide-induced biological actions such as interleukin-6 production. Lipopolysaccharide isolated from P. gingivalis was shown to use both TLR4 and a complex of TLR2 plus TLR1 or TLR6 to induce biological responses, PGE2, prostaglandin E2; IL, interleukin; LPS, lipopolysaccharide; MR. Toil-like receptor; TNFa, tumor necrosis factor a; TRAF6, TNF receptor associated factor 6 MyD88, myeloid differentiation factor 88; TIR domain, Toll I IL-1R domain; TRW, TIR domain-containing adaptor-inducing interferonb; TRAM, TRIF-related adaptor molecule (11).

IL 12 is regarded as a pro-inflammatory cytokine with immunoregulatory function, it may be greatly involved in chronic periodontitis.IL-12 acts not only as an activator of macrophages in the inflammed tissue, increasing their phagocytic and bacteriocidal activity, but also increases the ability of macrophages to produce IL 12 in a powerful positive feedback loop. It acts as both as an inflammatory mediator and also initiate host immune response within the periodontal tissues. (6) It was also suggested that IL-6 may act as an autocrine and/or paracrine factor in bone resorption in pathologic states by stimulating the formation of osteoclasts and the activation of osteoclastic bone resorptiond. (11) Locally secreted IL-8 induces neutrophil extravasation at the site of inflammation and that the numerous neutrophils present in the lamina propria and the epithelium of inflamed gingiva may be directed there by IL-8. (11)

Interleukins in Connective Tissue Destruction

An early event in pathogenesis of periodontal disease is dissolution of approximately 70% of gingival connective tissue. Collagen breakdown may occur by two pathways (intracellular and extracellular). ILI inhibit the intracellular pathway while stimulating extracellular route, induces the production of MMPs and elevated level of procollagenase in both gingival fibroblasts and periodontal ligament, stimulates the plasminogen activator in gingival fibroblast resulting in generation of plasmin which is naturally occurring activator for MMP.

Interleukins in Bone Destruction

Hausmann speculated that periodontal bone loss was multifactorial, "involving a series of interactions between agent in plaque and mediators in periodontal tissue. (12) Once "critical level of proinflammatory cytokine production is reached, a physiologic response become pathologic. If the inflammation occurs predominantly in the cementum, it will result in loss of attachment. If occurs near alveolar bone, bone loss occurs. If the inflammatory front does not progress far from the epithelium, the resulting lesion restricted to gingivitis.

PMN's and monocyte of innate immune response produce ILI and TNF a that produces bone resorption. IL6 causes bone resorption in pathological state by stimulating the formation of osteoclast and activation of osteoclastic resorption. 1L8 is potent chemotatic for leukocyte and induces extravasation of neutrophils at the site of inflammation. These neutrophils contribute to local tissue destruction and bone resorption of periodontal tissue. 1L17 which shown to stimulate endothelial cell, fibroblastic cell to produce IL6, IL8 and PGE2 which are good activator for RANKL production by osteoblast and thus influence on osteoclastic bone resorption.

Interleukins in Chronic Periodontitis

Chronic periodontitis is an inflammatory response in the periodontal tissues. Chronic periodontitis in adults typically follows a cyclical course, with some forms remaining stable over many years and other forms progressing with subsequent tooth loss despite extensive treatment. (13) The initial immune response in chronic periodontitis occurs following colonization of the gingival sulcus by periodontopathic bacteria. The presence of the bacteria induces the production of cytokines and chemokines by the gingival epithelium. This results in the expression of adhesion molecules, increased permeability of gingival capillaries and chemotaxis of polymorphonuclear neutrophils through the junctional epithelium and into the gingival sulcus. The specific cytokines and chemokines produced by this initial response lead to a perivascular T-cell / macrophage dominated inflammatory infiltrate in the connective tissues. If this cell-mediated immune response does not control the bacterial challenge, progression to a B-cell /plasma-cell lesion occurs. The antibodies subsequently produced may be protective and control the infection, or may be non-protective with resultant connective tissue destruction and bone loss. (14) The early / stable lesion of chronic periodontitis is dominated by macrophages and T-cells, suggesting that Th1 cytokines are important in the development of this response, while the advanced/progressive lesion of chronic periodontitis, which is characterized by B-cells and plasma cells, is dependent upon Th2 cytokines. (15) Thl cytokines include interleukin-2 and interferon-gamma and promote cell-mediated immunity, while the Th2 cytokine, interleukin-4, suppresses cell-mediated responses and enhances humoral immunity. A reduced Th l response has been shown in chronic periodontitis, where peripheral blood mononuclear cells obtained from patients with chronic periodontitis and then stimulated with mitogens, Porphyromonas gingivalis and Fusobacteriumnucleatum showed lower levels of Th1 cytokines(IL2,interferon gamma).Additionally, increased levels of Th2 cytokines (IL-4, IL-5, IL-6, IL-9, IL-10, and IL- 13) have been reported in GCF, gingival tissue (15) and peripheral blood of patients with chronic periodontitis. (16)

The role of interleukin-10 in human chronic infections is both complex and critical. It has been implicated in the pathogenesis of chronic periodontitis, is critical in controlling the balance between Thl cells and Th2 cells in chronic periodontitis, whereby an excess of interleukin-10 may shift the balance in favor of a Th2 response and progressive disease, whereas its shortage leads to increased interleukin-1 production and increased tissue destruction. (17) By contrast, high levels of IL 10 may even inhibit B-cell activation and proliferation, hence further illustrating its complex role. Low levels of IL-10 have been demonstrated in chronic periodontitis lesions compared with gingivitis, which may allow continued polyclonal B-cell activation to occur. (18)

Th17 cells are characterized by the production of interleukin-17. Th17 cell development depend upon the presence of interleukin-23 (a monocyte product) and also IL6 and TGF-b. Interleukin-17 expression is higher in chronic periodontitis tissues than in healthy tissues, along with IL-1b and TNF-a. (19) It induces the production of pro-MMP-1 and MMP-3 by gingival fibroblasts. In contrast, interleukin-17 receptor knockout mice showed increased P. gingivalis-induced periodontal bone loss, suggesting its possible protective role ingingivalis-induced tissue destruction. (20-22.)

IL-1 levels were elevated in GCF at periodontitis sites and that marked reductions of total IL-1 levels were observed following effective treatment. They also commented that IL-b was detected more frequently than IL-lex in GCF from untreated patients with periodontitis. (21)

Interleukins in Refractory Periodontitis

Reinhardt and colleagues (1993) reported that elevated levels of IL1a, IL-13, and IL-6 were detected in the GCF of patients with refractory periodontitis. A possible correlation among bleeding index, probing depth, and the IL-6 levels of the crevicular fluid has also been demonstrated. (21)

Interleukins in Aggressive Periodontitis

B-cell/plasma-cell nature of the aggressive periodontitis lesion makes it likely obe Th2mediated lesion. It has been shown that Th17 cells can be converted to Thl cells or Th2 cells under the influence of interleukin-12 or interleukm-4 respectively, while CD4+, CD25+,forkhead box P3 (Foxp3+) regulatory T-cells can be converted to an interleukin-17-producing cell when co-cultured with dendritic cells selectively activated via dectin-1. These latter findings highlight the complex regulatory networks that are probably operating in both chronic and aggressive peniodontitis. (23)

IL-8 is a chemoattractant for neutrophils expressing the receptor CXCR (1). Enhanced accumulation of neutrophils in the pocket epithelium and adjacent connective tissue of patients with chronic periodontitis and with generalized aggressive periodontitis (GAP)s was associated with the upregulation of IL8, intercellular adhesion molecule-1, IL-1b and TNF--a expression, which related to the severity and activity of generalized aggressive periodontitis. (24) Anne Havemose-Poulsen in 2005 compared Cytokine Profiles in Peripheral Blood and Whole Blood Cell Cultures Associated With Aggressive Periodontitis, Juvenile idiopathic Arthritis, and Rheumatoid Arthritis, found that two anti-inflammatory cytokines, IL10 and IL1Ra were significantly elevated in GAP patients and patients with aggressive periodontitis and type of arthritis presented with similar components of blood cytokine profiles distinguishing them from individuals free of disease. Interestingly, it has recently been shown that infection of human macrophages with A. actinomycetemcomitans (Aa), a bacterium associated with certain forms of aggressive periodontitis, results in the profound release of activeIL-1b, an effect considerably larger than that induced by LPSand not associated with enhanced secretion of interleukin-6 or TNF. The effect is mainly dependent on the leukotoxin from A. actinomycetemcomitans

Interleukin Polymorphisms and Periodontitis

The systemic immune response, genetic and environmental factors also affect the risk of developing periodontitis. In recent years, studies have demonstrated that periodontitis is associated with elevated levels of a variety of inflammatory biomarkers. Furthermore, genetic variants of some cytokines confer susceptibility to periodontitis. (3) As it is accepted that the immune system plays an important role in the pathogenesis of periodontitis, most genes that are considered to be responsible for the development of periodontitis are also linked to the immune response. These include the genes that affect the expression of IL1, IL-6, TNF-a, and IL10, E-selectins, Fc-gamma receptor, CD 14, toll-like receptors, caspase recruitment domain 15 and vitamin D receptor.1 Polymorphisms arises as result of insertion and deletion in nucleotide sequence. Genotype polymorphisms have also been associated with disease diagnosis, severity and presence of subgingival bacteria. IL8 and IL6 investigated for the relationship between periodontopathic bacteria (Aa &Pg) and bleeding on probing which shows that association is found in both aggressive and severe form of chronic periodontitis.

IL-1 Gene Polymorphism

IL-1 gene cluster is located on chromosome 2. The first study that reported polymorphism for IL-1 gene in relation to periodontitis was presented by Korman et al, in Caucasians. He concluded that IL-1 composite genotype could be considered a putative severity factor for periodontitis in Caucasians. Sensitivity and specificity of IL-1 "Genotype positive" model was depicted by Kornman et al, 1997. 1 Anne Havemose--Poulsen et al. demonstrate that in localized aggressive periodontitis patients, allele 2 of IL--1 RN VNTR(variable no. of tandem repeats) was associated with significantly higher levels of IL -1a, 6, 10 and TNF--a, whereas allele 2 of IL--1p +3954 was associated with significantly lower levels of the same cytokine.

IL-4 Gene Polymorphism

IL -4- polymorphism was at the promoter sequence-590 C/T, -33c/T and intron 3. VNTR of IL4 acted in a cooperative fashion andresulted in high production of IL 4. In 2008, Stefan Reichert et al studied the expression or IL-12 R p2 molecule in a crucial regulatory factor in the T helper type differentiation of T cells. They found that single nucleotide polymorphism of the flanking region of IL -12RB2 leads to a very weak cellular immune response. They reported that the frequencies of variant alleles of IL 12 RB2 were significantly higher in aggressive periodontitis patients.

IL-6 Gene Polymorphisms

Shao et al 2009, in the meta-analysis indicate that the IL-6,-174 G allele could not modify the risk of chronic periodontitis, but increased risk of aggressive periodontitis. And -572 C/G polymorphism is associated with the pathogenesis of periodontitis, as it predisposes to either chronic or aggressive periodontitis.

IL-10 Gene Polymorphisms

IL-10 gene is located on chromosome 1, in a cluster with closely related IL-genes IL-19, -24. IL-10 has an inhibitory effect on IL-1a, IL-1b, TNF-a, IL-6,8 and 12. Functional disturbances in IL-10 due to genetic polymorphisms could be detrimental to host tissue and linked to periodontal disease susceptibility.

Implant Failure And Interleukin Polymorphism

Regarding the timing of implant failure, it can be classified as early when osseointegration fails to occur, or late when the achieved osseointegration is lost after a period of function. Infection, overheating and impaired healing are the main factors associated with early failure of dental implants. Of these, surgical trauma, a consequence of implant insertion, initiates a local inflammatory response that includes the release and activation of a variety of cytokines and growth factors. This local factor production determines the quality of bone formation or the formation of fibrosis. Increased levels of bone resorptive interleukins, such as IL-1, might stimulate an excessive inflammatory response, affecting osseointegration success.

A few studies have analyzed the relationship between interleukin-1 genepolymorphisms and implant failure. Wilson & Nunn (1999) were the first to study the relationship between implant loss and the interleukin-1 composite genotype reported by Kornmanet at (1997) [allele Tat interleukin- IA (889) and at interleukin-1B [p3953) loci]. Their analysis failed to provide a positive correlation, but these results might have been influenced by variables, such smoking and the existence of late and early failure implants in the same sample. Rogers et al. (2002) also found no association between the same. Campos et al 2004 also showed that polymorphism in the interleukin-1 RN (intron 2), interleukin- 1B (511, p3953) and interleukin-1A (889) genes were not associated with early implant failure in a nonsmoking Brazilian population.

Interleukins as Diagnostic Marker

The biochemical assessment of periodontal disease can be accomplished using several approaches. The most practical and least-invasive, involves analysis of biologic fluids that are derived from the periodontal tissues or contain specific mediators that are present as a result of periodontal disease. The biologic fluids that have been studied to understand the nature of destructive periodontitis and to identify potential diagnostic markers of active disease include serum (blood), gingival fluid, and saliva.

Blood

Studies of serum antibody levels to periodontal bacteria were among earliest investigations demonstrating that a humoral immune response occurs in patients with periodontitis. More recent studies have demonstrated that patients with periodontitis have elevated antibody titers to subgingival pathogens. The levels of inflammatory cytokines (ie, IL-6) and general markersof inflammation (ie, C-reactive protein) have been shown to be elevated in the blood of patients with periodontitis. Nevertheless, serum markers of periodontitits, or of inflammation, are not currently used as diagnostic tests for periodontitis. (25)

Gingival Crevicular Fluid

GCF is a serum transudate, or more commonly inflammatory exudates, that emanates from the gingival crevice and can be collected from the crevice orifice. GCF has been analysed for diagnostic purposes. Its constituents are derived from a variety of sources including host as well as from microorganisms in the subgingival and supragingival plaque. The collection and analysis of GCF samples provides a non-invasive means to assess the pathophysiological status of the periodontium in a site-specific manner. According to Armitage (2004), more than 65 GCF constituents have been evaluated as potential diagnostic markers of periodontal disease progression. These markers can be divided into three groups: host-derived enzymes and their inhibitors, inflammatory mediators and host-response modifiers, and byproducts of tissue breakdown. The inflammatory cytokines in particular IL-1b, may play an integral role in the etiology of periodontal disease. Lieu et al (1996) demonstrated that with an increase in gingival index and probing, there was a corresponding increase in IL-1b in both the gingival tissue and GCF. Engebretson et al through a longitudinal study suggested that GCF IL-1b expression is genetically influenced and not solely a result of local clinical parameters. Also, a GCF level of 1L8 was found to be higher in periodontal diseases and was influenced by local IL1 beta activities. (26)

Interleukins as Anti-Inflammatory and Antiresorptive Therapy

As inflammatory cytokines are involved in inflammatory diseases associated with bone loss and have therefore become logical targets for the development of therapeutic agents. One of the first cytokines to be targeted was IL-1 as a result of its key regulatory role in bone resorption in diseases such as rheumatoid arthritis and periodontitis. In addition, agents targeting IL-3,6,15,12 and 23 have been studied. These anti-cytokine agents provide new opportunities to modulate host responses in inflammatory diseases. In particular, most seem to influence the secondary effects of cytokines on RANKL expression and therefore may not influence osteoclast-mediated bone resorption directly. Future efforts in this area, to ensure more effective control of pathologic bone resorption should try to target those cytokines that directly influence osteoclast formation and function. Surprisingly few studies have investigated the effect of interleukin antagonists on periodontitis. One study investigating inflammation and tissue loss in a nonhuman primate model of periodontitis using human soluble interleukin-1 receptor type 1 as an inhibitor of IL-1 reported that the inhibition of IL-1 has a significant effect on the reduction of inflammation, connective tissue attachment loss and bone resorption. Given the emerging use of these agents as anti-inflammatory and anti-resorptive agents, further investigations in experimental models of periodontitis are arranted. (27)

CONCLUSION

Interleukins are key modulators of inflammation. They participate in acute and chronic inflammation in a complex network of interactions. Several cytokines exhibit some redundancy in function and share overlapping properties and structure.Theseplay an important role in a number of different physiologic processes, but if expressed inappropriately, they also induce pathology. Under pathologic conditions such as those that occur in periodontal disease, the balance between pro- and anti-inflammation is directed towards proinflammatory activity.In periodontal tissue destruction three proinflammatory cytokines, IL-1, IL-6, and TNF-a, appear to have a central role.

Better understanding of the pathways regulated by interleukins will allow the identification and/or development of agents for improved modulation of the inflammatory response for the treatment of periodontitis autoimmune, infectious, and neoplastic diseases.

doi: 10.5866/2016.8.10018

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(39.) Fujita T, Ashikaga A, Shiba H, Kajiya M, Kishimoto A, Hirata R, Tsunekuni N, Hirono C, Kawaguchi H, Shiba Y, Kurihara H. Irsogladine maleate counters the interleukinI b- induced suppression in gap-junctional intercellular communication but does not affect the interleukin-lb-induced zonula occludens protein- I levels in human gingival epithelial cells. J Periodont Res 2008; 43:96-102.

(40.) Sudha Agarwal, Charu S Chandra, Nicholas P Piesco, Herman H Langkamp, Lathe Rowen, Coskun Raran. Regulation of Periodontal Ligament Cell Functions by Interleukin-Ib. Infection and Immunity 1998; 932-7.

(41.) Hosokawa Y Hosokawa I, Ozaki K, Nakae H, IVlatsuo T. Cytokines differentially regulate CXCLIO production by interferon-cestimulated or tumor necrosis factor a stimulated human gingival fibroblasts. J Periodont Res 2009; 44:225-31.

(42.) Steinberg T, Dannewitz B, Tomakidi P, Hoheisel JD, Munssig E, Kohl A, Nees M. Analysis of interleukin- lb-modulated mRNA gene transcription in human gingival keratinocytes by epithelia-specific cDNA microarrays. J Periodont Res 2006; 41:426-46.

(43.) Sung Woo Lee and Yun Sik Hong. Anti-inflammatory effects of IL-4 and IL-10 on Human Polymorphonuclear Leukocytes. J Korean Med Sci 2002; 17:7-14

(44.) Rawlinson A, Grummitt Walsh TF, and Douglas CWI. Interleukin I and receptor antationist levels in gingival crevicular fluid in heavy smokers versus non-smokers. J Periodontol 2003; 30:42-8.

(45.) Lester SR, Rain JL, Serio FG, and Johnson R.R. Relationship between the gingival sulcus depth and interleukin- I isoform concentrations within the adjacent gingival tissue. J Periodont Res 2009; 44:323-9.

(46.) Rachna Kaushik, R. K. Yeltiwar, and Kumar Pushpanshu. Salivary Interleukin-lReta Levels in Chronic Periodontitis Patients Before and After Periodontal Phase- I Therapy and Healthy Controls A Case-Control Study. Journal of Periodontology 2011; 82(9):1353-9.

Babitha GA [1], Disha Nagpal [2], Snehal J Shripad [3], Shiva Yadav [4], Shobha Prakash [5]

[1,2,3,4&5] Department of Periodontics College of Dental Sciences, Davangere, Karnataka, India

Article Info:

Received: January 9, 2016

Review Completed: February 12, 2016

Accepted: March 11, 2016

Available Online: May, 2016 (www.nacd.in)

Email for correspondence:

shivacharan08@gmail.com
Table 1: Classification of Cytokines

Pro-inflammatory       Anti-inflammatory    Chemokines
cytokines              cytokines

IL-1 b, IL-2, IL-6,    IL-4, IL-5, IL-10,   IL-8, MCP-1, MIP-1beta
IL-8, IL-12, IL- 17,   IL-13, TGF-b
IFN-g TNF-a

Table2: Interleukins Involved In Acute Inflammation

IL     Synonyms              Source                Includes

IL-1   endogenous            Mainly.               Group of
       pyrogen (EP),         Monocytes,            nine or more
       mononuclear           although other        proteins
       cell factor, and      cells may             consisting of
       lymphocyte            contribute in         ILIaIL-Ib, IL,
       activating factor     disease states.       antagonist
       (LAF)                 Microbial             (IL-Ira),
                             products such         IL-18 (also
                             as LPS or             called IL-
                             endotoxin,            Iy), and the
                             potently              recently
                             upregulate IL-l       cloned and
                             synthesis.            undetermined
                                                   ILl8, Il1 E,
                                                   ILI [pounds
                                                   sterling] IL-IH4,
                                                   ILT, and IL-
                                                   IHI.

IL 6   IFN-b2,               A variety of
       hybridoma/            cells including
       plasmacytoma          mononuclear
       growth factor,        phagocytes,
       hepatocyte-           T cells and
       stimulating factor,   fibroblasts.
       B cell stimulatory    Up-regulation
       factor 2 (BSF-        of IL-6
       2), and B cell        production has
       differentiation       been observed
       factor (BCDF).        in a variety
                             of chronic
                             inflammatory
                             and autoimmune
                             disorders. (1)

IL11                         Bone marrow
                             stromal cells
                             and by some
                             fibroblasts

IL-8   Neutrophil            A variety of          belong to a
       chemotactic           cells including       chemotactic
       factor Neutrophil     monocytes, T          cytokine
       activating protein    lymphocytes,          Family
       (NAP-1) serves        neutrophils,          protein.
       as a prototype        vascular
       for discussing        endothelial
       the biologic          cells, dermal
       properties of         fibroblasts,
       rapidly growing       keratinocyte,
       family of             hepatocytes, and
       inflammatory          human gastric
       mediators             cancer cells. The
                             production is not
                             constitutive but
                             occurs ordinarily
                             in the presence
                             of inflammatory
                             stimuli such as
                             LPS, IL-1, and TNF.

IL-    originally            unusual               The only
16 1   identified as         cytokine-             member
       a chemotactic         preformed             of the "C"
       factor known          IL-16 is stored       family of
       as lymphocyte         in CD8+               chemokines.
       chemoattractant       lymphocyteand
       factor or             is secreted upon
       lymphotactin.         stimulation
                             with histamine /
                             serotonin.

IL17                         is a product
                             of activated T
                             lymphocytes

IL     Genes Mapped to   Structure         cDNA
       Chromosome

IL-1   Long arm of                         cDNAs for
       chromosome                          IL-1a and b
       2, except IL-                       were cloned in
       18.28                               1984. They are
                                           encoded by two
                                           different genes,
                                           both located
                                           on human
                                           chromosome
                                           2. Their size
                                           ranges from
                                           22-31 kDa for
                                           cell-associated
                                           molecules, and
                                           17.5 kDa for
                                           the secreted
                                           molecule

IL 6   Chromosome        Glycoprotein      cDNA was
       7 in humans       ranging from      cloned in 1986
                         21 to 28 (Da
                         depending on
                         the degree
                         of post-
                         translational
                         modification.

IL11   Located on        Molecular         cDNA was
       the long          weight24 kDa      cloned in 1990.
       arm of
       chromosome
       19

IL-8   Chromosome        Consists of 72    cDNA was
       4 in humans       amino acids       cloned by
                         in its mature     three different
                         form, is          laboratories
                         identified as a   between 1987
                         basic heparin-    and 1989
                         binding
                         protein

IL-    human
16     chromosome
(1)    1.

IL17                                       human IL-17
                                           cDNA was
                                           cloned in
                                           1995 based on
                                           homology with
                                           murine CTLA8
                                           1.9 Kb cDNA
                                           was found to
                                           encode a protein
                                           of 17.5 kDa
                                           homologous to
                                           a product of
                                           Herpes virus
                                           saimiri (HVS13).

IL     Function

IL-1   Critical for innate
       immunity involving
       responses to agents. (28)
       Both IL-1a and IL-lb
       can trigger fever by
       enhancing prostaglandin
       E2 (PGE2) synthesis by
       various endothelium of
       the hypothalamus and
       can stimulate T cell
       proliferation. IL-1 elicits
       the release of histamine
       from mast cells at the
       site of inflammation
       which triggers early
       vasodilatation and
       increase of vascular
       permeability. (1)

IL 6   The stimulation of
       acute phase protein
       synthesis by the liver,
       IL-6 acts as a growth
       factor for mature
       B cells and induces
       their final maturation
       into antibody-
       producing plasma
       cells. It is involved in
       T--cell activation and
       differentiation, and
       participates in the
       induction of IL- 2 and
       IL-2 receptor expression.
       Some of the regulatory
       effects of IL-6 involve
       inhibition of TNF
       production, providing
       negative feedback
       for limiting the acute
       inflammatory response (1)

IL11   A functional homologue
       of IL6 and can
       replace IL-6 for the
       proliferation of certain
       plasmacytoma cell lines
       and in the induction
       of acute phase protein
       secretion in the
       liver. Stimulation of
       T cell-dependent B
       cell immunoglobulin
       secretion, increased
       platelet production,
       and induction of IL-6
       expression by T cells. (1)

IL-8   Responsible for the
       chemotactic migration
       and activation of
       neutrophils and
       other cell types
       (such as monocytes,
       lymphocytes, and
       eosinophils) at sites of
       inflammation. Its main
       inflammatory impact
       lies in its chemotactic
       effects on neutrophils
       and its ability to
       stimulate granulocyte
       activity. enhancing
       neutrophil adherence
       to endothelial cells
       and facilitating their
       diapedesis through
       vessel walls. 1Thus,
       IL-8 mediates
       the recruitment
       and activation of
       neutrophils in inflamed
       tissue. (29)

IL-    Induces chemotaxis of
16     CD4+ T lymphocytes
(1)    and is believed to
       initiate T-cell mediated
       inflammation in asthma. (1)

IL17   Stimulation of IL-6
       and IL-8 production
       and enhanced ICAM1
       expression on human
       foreskin fibroblasts. (1)

Table 3. The cytokines known to mediate chronic inflammatory processes
can be divided into (1)

Participating in humoral              Contributing to cellular
inflammation                          inflammation

IL-3, IL-4, IL-5, IL-6, IL-7, IL-9,   as IL-1,IL-2,IL-3, IL-4, IL-7,
IL-10, IL-13, and transforming        IL-9, IL-10, IL-12, interferons
growth factor-b (TGF-b)               (IFNs), IFN-g inducing factor
                                      GF-b, and TNF-a and -b.

Table 4: Interleukin Involved In Chronic Inflammation

IL          Other Name          Source

IL2         Originally          Mainly by
            known as T cell     activated T
            growth factor       helper cells.
            (TCGF).

IL3         multi-CSF           activated T
                                cells and mast
                                cells

IL4                             CD4+
                                Thcells, mast
                                cells,
                                basophils.

IL5         as B cell           produced by
            growth factor II    CD4+ T helper
            (BCGFII) and        cells well as
            T cell replacing    NK cells
            factor (TRF)

IL-7 (30)                       IL-7, a
                                cytokine
                                purified as
                                a pre-B cell
                                growth factor,
                                is a bone
                                marrow and
                                thymic stromal
                                cell product

IL 9 (31)   Was known           CD4 T helper
            as mast             (TH2) cells as
            cell growth-        well as some B
            enhancing           lymphomas.
            activity (MEA)      Its production
            and murine          is IL-4 and
            T-cell growth       IL-10, and
                                thus IL-2-
                                dependent

IL 10 (1)   B cell-derived      Produced by
            T cell growth       a variety of
            factor Cytokine     cell types,
            synthesis           Including
            inhibitory          CD4+ T cells,
            factor (CSIF)       activated
            because it          CD8+ T cells,
            inhibits IFN1-g     and activated
            production by       B cells
            activated T
            cells.

            IL-10 is
            considered a
            T cell cross-
            regulatory
            factor and
            has thus been
            referred to as an
            "anticytokine".

IL13        Originally
            identified
            as a protein
            produced by
            activated
            murine Th2
            lymphocytes
            and referred to
            as P600 (K D.
            Brown 1989).

IL14 (1)                        A product of
                                malignant B
                                and T cells as
                                well as normal
                                T cells.

IL 12       Natural killer      originally
            cell stimulatory    isolated from
            factor (NKSF)       Epstein-
            and cytotoxic       Barr virus
            lymphocyte          transformed B
            maturation          cells.
            factor (CLMF),      secreted by activated
                                B cells,
                                macrophages,
                                and other
                                antigen
                                presenting
                                cells (APCs)
                                but its
                                production is
                                inhibited by
                                IL-4 and IL-10

IL15 (1)    Originally          produced by
            discovered          activated
            as a T cell         monocyte,
            stimulatory         epithelial cells,
            activity            and fibroblasts

IL          Genes mapped to chromosome   Structure

IL2         Long arm of                  15 kDa
            chromosome 4.                glycoprotein

IL3         localized to                 The molecular
            chromosome 5                 weight of IL-3
                                         ranges from
                                         14 to 36 kDa

IL4         Human                        Expressed as
            chromosome5                  a 15-19 kDa
                                         protein and
                                         exists as a
                                         dimer

IL5         chromosome 5                 a protein of
            in humans.                   20-22 kDa
                                         which has
                                         an apparent
                                         molecular
                                         weight of 45
                                         kDa upon
                                         dimerization.
                                         Exists as a
                                         dimer linked
                                         bonds.

IL-7 (30)   Human                        25 kDa
            chromosome 8

IL 9 (31)   human
            chromosome 5

IL 10 (1)                                18kDa protein

IL13        Human                        12-17 kDa
            chromosome5,                 protein
            closely linked
            to the gene
            encoding IL-4

IL14 (1)                                 53 kDa growth
                                         factor (BCGF)

IL 12                                    It is a
                                         heterodimer
                                         composed of
                                         two subunits
                                         of 35 and 40
                                         kDa.

IL15 (1)    Chromosome4                  Approximately
                                         15 kDa
                                         not exhibit
                                         any sequence
                                         homology with
                                         IL-2

IL          cDNA

IL2         The human
            IL-2 cDNA was
            cloned in 1983

IL3         The cloning
            of the
            corresponding
            Cdna was
            reported in 1984

IL4         cDNA was
            cloned in 1986.

IL5         is cloned in 1987

IL-7 (30)   cDNA was
            cloned in 1989.

IL 9 (31)   cDNA was
            cloned in 1989

IL 10 (1)   The cDNA for
            human IL-10
            was cloned in
            1990

IL13        The cDNA for
            IL- 13 was
            recently cloned

IL14 (1)

IL 12       cDNAs for both
            subunits were
            cloned in 1991

IL15 (1)

IL          Function

IL2         Acts as a growth factor/activator
            for T cells, NK cells, and B cells
            and promotes the development
            of lymphokine-activated killer
            (LAK) cells. It therefore plays a
            critical role in regulating both
            cellular and humoral chronic
            inflammatory responses. Binding
            of IL-2 to the IL-2 receptor on
            T lymphocytes leads to cell
            proliferation, increased lymphokine
            secretion(IFNg, lymphotoxin, IL-4,
            IL-3, IL-5, GM-CSF), and enhanced
            expression of class II MHC
            molecules. (1)

IL3         --Stimulates eosinophils and B cell
            differentiation

            --Inhibits lymphokine activated killer
            (LAK) cell activity.

            --IL-3 shares activities with GM-
            CSF,not only stimulates the effectors
            Ieucocytes, but can also regulate their
            localization to inflammatory sites by
            the acting on endothelium.

            --The ability of IL-3 to enhance MHC
            class II expression is not limited
            to monocytes, eosinophils and
            neutrophils but also encompasses
            endothelial cells.

            --stimulates secretion of the
            circulating cytokines IL-6 and G-CSF
            by the vascular endothelium suggests
            an alternative, indirect mechanism
            by which IL-3 could influence
            haemopoiesis in the bone marrow. (23)

IL4         It induces CD4+ T cells to
            differentiate into TH2 cells while
            suppressing the development of Th1
            cells.

            It also acts as a B cell, T cell, and
            mast cell growth factor, it enhances
            class II MHC expression on B cells,
            and it promotes immunoglobulin class
            switching to IgG 1 and IgE. In fact,
            IL-4 is necessary for IgE response
            induction, and its absence also leads
            to significantly lower levels oflgGl in
            T cell-dependent immune responses.

            The stimulatory effect of IL-4 on IgG1
            and IgE production and on MHC class
            II induction are down-regulated by
            IFN-g, a cytokine whose functions are
            antagonized by IL-4 and vice versa.

            IL-4 also stimulates collagen and
            IL-6 production by human dermal
            fibroblasts, and may thus play a
            role in the pathogenesis of fibrotic
            diseases such as systemic sclerosis.

IL5         Involved in eosinophil differentiation
            and activation and stimulation of
            immunoglobulin class switching
            to IgA. It also includes increased
            activation of B cell proliferation and
            enhancement of T cell cytotoxicity.
            The combined production of IL-4 and
            IL-5 by CD4+ Th2 cells. Therefore,
            results in IgE and IgA production and
            mast cell and eosinophil stimulation. (1)

IL-7 (30)   It stimulates the development of
            pre-B and pre-T cells and acts as a
            growth factor for B cells, T cells, and
            early lymphocytes.

IL 9 (31)   Involved in early hematopoietic
            ontogeny, can influence pro
            inflammatory cytokines such as
            TNF, ILI, INF and also affect
            differentiation and functioning of
            both Th17 and Treg cells.

            IL9- mediated signaling responses
            have been dependent on the Janus
            kinase (JAK-1)-signal transducer and
            activator of transcription pathways.
            15is regulatory in nature in that it
            inhibits lymphokine production by
            IFN-g-producing CD4+ T cells and
            enhances the growth of CD8+ T
            cells. In addition, IL-9 promotes the
            production of immunoglobulins by
            B cells and the proliferation of mast
            cells.

IL 10 (1)   -Reduction of antigen-specific T
            cell proliferation, Inhibition of IL-
            2-induced IFN-g production by NK
            cells, and inhibition of IL-4 and IFN-g
            induced MHC class II expression
            on monocytes. Since IL-10 can be
            produced by TH2 cells and inhibits
            TH1 function by preventing TH1
            cytokine production (such as IFN-g
            IL-10 also acts as a co-differentiation
            factor for cytotoxic T cells and a co-
            factor for T cell growth.

            Human IL-10 (hIL-10) shares 84%
            identity at the amino acid level with
            a homolog, viral IL-10 (vIL-10), which
            is encoded by the Epstein-Barr virus.
            vIL- 10 shares will hiLe10 inhibitory
            effects on cytokine production and
            stimulatory effects on B cell growth. (1)

IL13        IL-13 exhibits anti-inflammatory
            activities by inhibiting the production
            of inflammatory cytokines, such as
            IL-lb, TNF-a, IL- 8, and IL-6, by
            human peripheral blood monocytes
            induced with LPS.

            Inhibition of inflammatory cytokine
            production is also a characteristic of
            two other cytokines produced by TH2
            lymphocytes, namely IL-4 and IL-10.
            In addition, IL-13 enhances monocyte
            and B lymphocyte differentiation
            and proliferation, increases CD23
            expression, and induces IgG4 and IgE
            class switching. (1)

IL14 (1)    Induce B cell proliferation. However,
            IL-14 inhibits immunoglobulin
            secretion.

            It has been suggested to play an
            important role in the aggressive
            form of B-cell type non-Hodgkin's
            lymphoma. (1)

IL 12       The biological activities include
            enhancement of cytotoxic T cells
            and lymphokine activated 'killer
            (LAK) cell generation and activation,
            increased natural killer (NK) cell
            cytotoxicity, induction of activated
            T cell and NK cell proliferation,
            induction of IFN-g production by
            NK cells and T cells, and inhibition
            of IgE synthesis by IL-4-stimulated
            lymphocytes via IFN-g-dependent
            and independent mechanisms.

            In addition, the stimulatory effect
            of IL-12 on Th1 development is
            antagonized by IL-4, a cytokine which
            promotes Th2 cell development.
            Therefore, IL-12 plays an important
            role in cell-mediated inflammation
            and also contributes to the regulation
            of immunoglobulin production. (1)

IL15 (1)    Shares many biologic properties with
            IL-2 and mediates its activity via a
            multi-subunit high affinity receptor
            comprised of a unique alpha chain
            and the beta and gamma chains of
            the IL-2R.

            It stimulates T lymphocyte and NK
            cell proliferation, as well as CTL
            and LAK activity. It enhances B
            cell expansion and immunoglobulin
            production. It is also a T lymphocyte
            chemoattractant. IL-15 may be
            responsible for the recruitment
            and activation of T lymphocytes
            in the synovium of patients with
            rheumatoid arthritis where its levels
            have been found to be elevated.

Table 5: Review of Literature

AUTHORS AND YEAR                   STUDY

1. Carol A. Feghali et al          Review
1997 (1)

2. H. Okada and S.Murakami         Review
1998 (2).

3. Bosshardt DD et al 2005 (3)     Review

4. Yen-chung. Et al 2010 (6)       Review

5. Bartold PM et al 2000 (7)       Review

6. J.A. bochla et al 2008 (28)     Review

7. Baggiolini et al 2008 (32)      Review

8. Akihisa Harada et al 1998       Review
(33)

9. EijaIKorpelainen et al          Review
2003 (23)

10. D.T. Grave, D. Cochrane (34)   Review

11. John J. Taylor 2010 (10)       Review

12. Masanori Koide et al 2010      Review
(11)

13. K.V.Arun, Avaneendra           Review
Talwar, T.S.S.Kumar 2011
(35)

14. Gemmell E, Yamazaki k,         Review
Seymour GJ. 2007 (36)

15. Gemmell E, Yamazaki K,         Review
Seymour GJ 2002 (37)

16. Palmqvist P et al 2008 (8)     In vitro Cell
                                   culture

17. R.G.Goodwin et al 1989 (30)    In vitro Cell
                                   culture

18. F.Q. Cunha et al 1999 (38)     In Vitro Cell
                                   culture

19. SudhaAgarwal et al 1985 (34)   In Vitro Cell
                                   culture

20. Fujita T, Ashikaga A, et al    In vitro
2008 (39)

21. SudhaAgarwal 1998 (40)         In vitro

22. Hosokawa Y 2009 (41)           In vitro

23. Steinberg T et al 2006 (42)    In vitro

24. Sung Woo Lee et al 2002 (43)   In vitro

25. Rawlinson A, 2003 (44)         In vivo

26. Lester SR, 2009 (45)           In vivo

27. Kaushik R et al 2011 (46)      In vivo

AUTHORS AND YEAR                   RESULTS

1. Carol A. Feghali et al          This review describes the role of
1997 (1)                           cytokines those involved in acute
                                   inflammation and those responsible
                                   for chronic inflammation and also
                                   summarizes features of the cell-
                                   surface receptors that mediate the
                                   inflammatory effects of the
                                   described cytokines.

2. H. Okada and S.Murakami         In this review, summarized the
1998 (2).                          information regarding cytokine
                                   expression in the periodontium and
                                   its possible relationship with
                                   tissue homeostasis and
                                   inflammatory disease progression.

3. Bosshardt DD et al 2005 (3)     --

4. Yen-chung. Et al 2010 (6)       Its summary of the overall
                                   contributions and balance of
                                   cytokines during periodontal
                                   infection.

5. Bartold PM et al 2000 (7)       Describe the interleukins
                                   according to Molecular and cell
                                   biology of the gingiva.

6. J.A. bochla et al 2008 (28)     Interleukin 1 Signal Transduction
                                   in Periodontitis

7. Baggiolini et al 2008 (32)      This review describe about
                                   Chemokines in pathology and
                                   medicine

8. Akihisa Harada et al 1998       IL-8 plays a causative role in
(33)                               acute inflammation by recruiting
                                   and activating neutrophils

9. EijaIKorpelainen et al          IL-3 was found to regulate
2003 (23)                          endothelial responses related to
                                   inflammation, immunity and
                                   haemopoiesis. These findings,
                                   summarized in this review, offer
                                   new insight into the physiological
                                   function of IL-3 and may also be
                                   of clinical importance, as IL-3
                                   is used in bone marrow
                                   reconstitution following cancer
                                   therapy.

10. D.T. Grave, D. Cochrane (34)   The contribution of IL-1 and TNF
                                   to periodontal destruction

11. John J. Taylor 2010 (10)       Cytokine regulation of immune
                                   responses to
                                   Porphyromonasgingivalis.

12. Masanori Koide et al 2010      In this review, summarize the
(11)                               mechanism by which osteoblasts and
                                   bone marrow stromal cells regulate
                                   osteoclast differentiation and
                                   function, and the bacterial
                                   strategy for bone resorption in
                                   periodontitis and further describe
                                   possible therapeutic approaches
                                   that may be used to prevent
                                   alveolar bone loss in
                                   periodontitis.

13. K.V.Arun, Avaneendra           This review focuses on the
Talwar, T.S.S.Kumar 2011           subsets, including the recently
(35)                               identified cells of the CD4
                                   lineage, their activation pathways
                                   and effectors function in
                                   periodontal disease. The roles of
                                   Th 17 and regulatory T (Treg)
                                   Cells in disease pathogenesis have
                                   been explored. Newer Th subsets
                                   such as Th9 and Th22 cells and
                                   their potential role in
                                   periodontal disease have also been
                                   outlined.

14. Gemmell E, Yamazaki k,         This review focuses on the role of
Seymour GJ. 2007 (36)              T cells in periodontal disease,
                                   homeostasis and autoimmunity.

15. Gemmell E, Yamazaki K,         The roles of interleukin (IL)-1,
Seymour GJ 2002 (37)               prostaglandin (PGE 2) and
                                   metalloproteinases as the
                                   destructive mediators in
                                   periodontal disease were largely
                                   understood, the control and
                                   regulation of these cytokines
                                   remained controversial. Two
                                   apparently conflicting theories
                                   have emerged. One is based on
                                   direct observations of human
                                   lesions, while the other is based
                                   on animal model experiments and
                                   the inability to demonstrate IL 4
                                   mrna in gingival extracts. As part
                                   of the "Controversy" series, this
                                   review is intended to stimulate
                                   debate and hence may appear in
                                   some places provocative.

16. Palmqvist P et al 2008 (8)     IL-b and TNF-a regulate IL-6 type
                                   cytokines in gingival fibroblasts.

17. R.G.Goodwin et al 1989 (30)    Human interleukin 7 regulate the
                                   molecular cloning and growth
                                   factor activity on human and
                                   murine B-lineage cells.

18. F.Q. Cunha et al 1999 (38)     The effect of IL-4 on responses to
                                   intraplantar (i.pl.) Carrageenin
                                   bradykinin, tnfa, IL-1b, IL-8 and
                                   PGE2 was investigated in a model
                                   of mechanical hyperalgesia in rats.
                                   Also, the celluar source of the
                                   IL-4 was investigated. And data
                                   suggest that IL-4 released by mast
                                   cells limits in amatory
                                   hyperalgesia. During the early
                                   phase of the in ammatory response
                                   the mode of action of the IL 4
                                   appears to be inhibition of the
                                   production tnfa, IL-1b and IL-8.
                                   In the later phase of the
                                   response, in addition to
                                   inhibiting the production of
                                   pro-in ammatory cytokines, IL 4
                                   also may inhibit the release of
                                   pgs.

19. SudhaAgarwal et al 1985 (34)   Functional Role of Interleukin 1
                                   in Periodontal Disease; Induction
                                   of Interleukin 1 Production by
                                   Bacteroidesgingivalis
                                   Lipopolysaccharide in Peritoneal
                                   Macrophages from C3H/hen and
                                   C3H/hej Mice

20. Fujita T, Ashikaga A, et al    Irsogladine maleate counters the
2008 (39)                          interleukin- 1b- induced
                                   suppression in gap- junctional
                                   intercellular communication but
                                   does not affect the
                                   interleukin-1b- induced
                                   zonulaoccludens protein-1 levels
                                   in human gingival epithelial
                                   cells.

21. SudhaAgarwal 1998 (40)         Induction of Interleukin 1
                                   Production by
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                                   Lipopolysaccharide in Peritoneal
                                   Macrophages from C3H/hen and
                                   C3H/hej Mice

22. Hosokawa Y 2009 (41)           Cytokines differentially regulate
                                   CXCL 10 production by
                                   interferon-c-stimulated or tumor
                                   necrosis factor-a stimulated human
                                   gingival fibroblasts.

23. Steinberg T et al 2006 (42)    Analysis of
                                   interleukin-1b-modulated mrna gene
                                   transcription in human gingival
                                   keratinocytes by epithelia
                                   -specific cdna microarrays.

24. Sung Woo Lee et al 2002 (43)   Anti-inflammatory effects of IL-4
                                   and IL-10 on Human
                                   Polymorphonuclear Leukocytes.

25. Rawlinson A, 2003 (44)         Interleukin 1 and receptor
                                   antagonist levels in gingival
                                   crevicular fluid in heavy smokers
                                   versus non -smokers.

26. Lester SR, 2009 (45)           Relationship between the gingival
                                   sulcus depth and interleukin -1
                                   insoform concentrations within the
                                   adjacent gingival tissue.

27. Kaushik R et al 2011 (46)      Interleukin-1 Beta Levels in
                                   Chronic Periodontitis Patients
                                   Before and After Periodontal
                                   Phase I Therapy and Healthy
                                   Controls-A Case- Control Study
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Author:Babitha, G.A.; Nagpal, Disha; Shripad, Snehal J.; Yadav, Shiva; Prakash, Shobha
Publication:Indian Journal of Dental Advancements
Date:Jan 1, 2016
Words:8754
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