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��ࡱ�>��	Z]����WXY�����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������_�	����bjbj,E,E	8�N/N/�,���������XXXXX����lll8��0�l�uT���������r�r�r�r�r�r�r$�w��zB�rmX������rXX���Ru%+%+%+��X�X��r%+��r%+%+J�f�-n������aR��������%.qiB�rhu0�u�iz�z�(n�z�-n-nJ�zXwn4��%+������r�r%+����u�������������������������������������������������������������������������z���������� :	Anticytokine Therapy- The Newer Horizons Revisited
Abstract
In the recent era of molecular biology, the focus on the progression of periodontitis is mainly on inflammatory mediators such as cytokines initiated due to microorganisms. Cytokines like Interleukin-1, Interleukin-6, tumor necrosis factor-�, matrix metalloproteinases and prostaglandin E2 play a vital role in alveolar bone destruction and extracellular matrix degradation in the pathogenesis of periodontitis. Hence the concept of inhibition of cytokine production or action through anti-cytokine therapy is implicated in various immune and inflammatory disorders and periodontitis. In the current scenario, the concept of anti-cytokine therapy has grabbed quite an attention when compared to other existing treatment strategies for immune and inflammatory disorders. The present article reviews on the comprehensive appraisal of the newer aspects of anticytokine therapy and it�s applications in periodontology.
Key words: cytokines, anticytokines, host modulation, soluble receptors, signaling pathways, rheumatoid arthritis, periodontitis
Introduction
Periodontitis is a chronic inflammatory disease caused primarily by bacteria in dental plaque, affecting the supporting structures of the teeth.[1] Specific periodontal pathogens such as the gram-negative anaerobic bacteria inhabiting within the sub-gingival plaque are associated with the progressive form of the disease.  Although bacteria are the major etiological agents, the host immune response to these bacteria is of fundamental importance.[2, 3]  Hence, it is evident that periodontitis is a multifactorial disease, affiliates with specific microorganisms, social and behavioral factors, genetic or epigenetic trait, all of which are modulated and controlled by the underlying immune and inflammatory responses of the host. Inflammation in periodontitis causes elevated T-lymphocytes, neutrophils, monocytes and dendritic cells at the inflammatory site and gets activated by virulence factors, antigens (lipopolysaccharides) or products from bacteria. These activated cells secrete pro-inflammatory cytokines and inflammatory mediators like IL-1� (Interleukin-1 �), IL-6 (Interleukin-6), TNF-� (Tumor necrosis factor- �), IL-7 (Interleukin-7), IL-17 (Interleukin-17), MMPs (matrix metalloproteinases) and PGE2 (prostaglandin E2), which accelerate osteoclastic development and activities through RANK/ RANKL (Receptor activator of nuclear factor kappa B/ Receptor activator of nuclear factor kappa B ligand) pathway, leading to alveolar bone destruction and extracellular matrix degradation.[4] Host modulation therapy is one of the modalities to prevent and treat periodontal diseases by regulating the                        pro-inflammatory cytokines and inflammatory mediators.[5, 6] Therefore the use of anticytokine therapy along with conventional treatments such as scaling and root planing has shown to be advantageous.[7]
Cytokines
Cytokines are soluble proteins, produced by nucleated cells throughout the body especially from lymphocytes (majorly T cells), monocytes, macrophages and granulocytes and also by epithelial cells, endothelial cells and fibroblasts.[4, 8] They play a central role in the pathogenesis of various inflammatory diseases, including periodontal diseases. It has been postulated that "appropriate" cytokine production results in protective immunity, while "inappropriate" cytokine production leads to tissue destruction and disease progression (Table 1). Cytokines have a tremendous built-in biological redundancy, such that many cytokines have overlapping functions. Hence, the overall biological effect is the result of the balance between all cytokines, rather than their individual levels.[4, 7]
Table 1: Functional classification of cytokines.[8, 9]
FamilyMembers*Hematopoietic IL-3, G-CSF, GM-CSF, M-CSF, EPO, SCFPro-inflammatoryIL-1�, IL-1�, 6, 17,  TNF�, LT, LIFAnti  inflammatoryIL-1R�, 4, 10, 13Growth and DifferentiationPDGF, TGF �, VEGF, EGF, FGF, IGF,ImmunoregulatoryTGF �, IFN, IL 2, 4, 5, 7, 9 18Chemotactic	IL-8, MIP-1�, MIP-1�, MCP-1, RANTES
*IL-interleukin; G-CSF-granulocyte colony stimulating factor; GM-CSF- granulocyte-macrophage colony stimulating factor; M-CSF - macrophage colony-stimulating factor; EPO - erythropoietin; SCF - stem cell factor; TNF - tumor necrosis factor; LT-lymphotoxin; LIF -leukemia inhibitory factor; IL-1Ra-interleukin-1 receptor antagonist; PDGF - platelet-derived growth factor; TGF - transforming growth factor; VEGF -vascular endothelial growth factor. EGF - epidermal growth factor; FGF - fibroblast growth factor; IGF - insulin-like growth factor; IFN - interferon; ; MIP - macrophage inflammatory protein; MCP - monocyte chemotactic protein; RANTES - regulated upon activation, normal T cell expressed and secreted; Modified from Arend WP[8, 9] 
Cytokines act through receptors, which are located on the cell surface. These receptors are membrane bound receptors (signal transducers), and when shed from cell surface by proteolytic enzymes, they are called soluble receptors (Table 2). Soluble receptors of certain cytokine acts as antagonists or agonists to respective membrane bound receptors of cytokines by downregulating (prevents downstream signaling) or transactivating mechanisms (activates non responsive cells) respectively (Table 3).[2, 7, 10] 
Cytokines bind to specific receptors on target cells and initiate intracellular signaling cascade, this causes alteration in gene regulation and activation thereby releasing secondary mediators like matrix metalloproteinases and prostaglandin E2. These mediators cause connective tissue breakdown and bone resorption.[3] IL-1�, IL-1�, TNF-�, IL-6 are pro-inflammatory cytokines, produced for prolonged periods at local inflammatory sites, essential for the initiation of periodontitis and its progression.[11]
IL-1 is a pro-inflammatory cytokine, sub divided into IL-1�, IL-1�, both are synthesized as 31KDa precursors, and these both have a large difference in post translational modifications.   IL-1� is biologically active, cleaved to a small extent. IL-1� needs a proteolytic cleavage and intra-cellularly activated by specific enzymes like caspases, and it is a potent stimulator of matrix metalloproteinases and prostaglandin E2.[11, 12] Hence, IL-1 � has a central role in mediating a variety of inflammatory responses. IL-1 � binds to membranous receptors on target cells. These receptors are Type I IL-1R and Type II IL-1R. Type I IL-1R is a primary signaling receptor along with IL-1R associated proteins (IL-1RAcP). Type II IL-1R is a decoy receptor and does not transduce any signals due to its short cytoplasmic tail.[2]
TNF-� is also a pro-inflammatory cytokine, produced mainly by macrophages and has a capacity to induce bone resorption and upregulate PGE2, MMPs and adhesion molecules on leukocyte and stimulate the production of chemokines finally resulting in severe inflammatory response. These effects are mediated through membranous bound tumor necrosis factor-receptor (mTNF-R). There are Type I TNF-R (55kDa molecular weight) and Type II TNF-R (75kDa molecular weight) and differ with each other in their intracellular domain, thereby produce different cellular responses. TNF-� binds to these receptors with high affinity and produces downstream signaling through mitogen activated protein (MAP) kinases and nuclear factor kappa B (NF-kB) activation cascades. TNF-R associated factor domain, death domain containing adapter proteins and associated signaling enzymes are responsible for initiating signaling by above mentioned cascades and these are specific for TNF- � signaling.[7] By action of proteolytic enzymes on the cell membrane, TNF-R shed from the cell surface. These shed receptors are soluble (sTNF-R) in various biological fluids and act as antagonist to TNF- � by preventing the binding of TNF to mTNF-R. There exist a vast evidence in literature suggesting the higher levels of sTNF-R that are detected in inflammatory conditions like periodontitis.[2, 5-7, 13]
 IL-6 is another important pro-inflammatory cytokine, responsible for various biological activities in most of the cells. IL-6 acts via ligand binding receptor (IL-6R) and signal transducer glycoprotein-130 (gp-130), located on the cell membrane. The cytosolic signaling pathways involved in IL-6 initiation includes Janus associated kinases (JAKs), signal transduce and activator of transcription 3 (STAT3) and mitogen activated protein kinase (MAPK) pathways. In contrast to other cytokine soluble receptors, soluble forms of IL-6 receptors are agonist to ligand binding IL-6 receptor. However soluble form of glycoprotein-130 (gp-130) has antagonistic effect to IL-6R (Table 3) and it contains only single domain. Therefore it can release in large amounts and can act as endocrine cytokine, activate liver to produce acute phase proteins and also activate hypothalamus for thermo-regulation. [4, 7, 14-16]





Table 2: Pro inflammatory Cytokines and it�s membrane and soluble receptors [4, 7, 10, 14- 16]
CytokinesMembrane receptorsSoluble receptors
IL-1�IL-1RI
IL-1RII
IL-1RAcPsIL-1RI
sIL-1RII
TNF-�TNF-RI 
TNF-RII sTNF-RI
sTNF-RII
IL-6IL-6R
Glycoprotein-130
sIL-6R
*IL-interleukin; IL-1R-interleukin-1 receptor; IL-1RAcP -interleukin-1 receptor associated protein; sIL-1RI- soluble interleukin-1 receptor; TNF - tumor necrosis factor; TNF-R- tumor necrosis factor receptor; sTNF-RI- soluble tumor necrosis factor receptor; IL-6R- interleukin-6 receptor; sIL-6R- soluble interleukin-6 receptor.
Anti- inflammatory cytokines
Inflammatory mediators that lead to bone resorption depend on the expression of                     pro-inflammatory cytokines, and to the contrary, anti-inflammatory cytokines, such as IL-4,    IL-10, IL-12, IL-13, and IL-18, serve to inhibit bone resorption.[12] Inlerleukin-1 receptor antagonists (IL-1Ra) competitively block the IL-1 binding without activating signaling pathways through binding, specifically to cell surface receptors such as IL-1RI with high affinity and not to the IL-1R associated proteins.[13] IL-4 potent anti- inflammatory cytokine, decreases osteoclastogenic activity of osteoblasts and directly targets osteoclast progenitor cells thereby decreases bone resorption. IL-10 decreases RANKL and increases osteoprotegrin (OPG) thereby inhibits bone resorption.[4, 14-16] IL-11 decreases tissue destruction by stimulation of a tissue inhibitor of matrix metallo proteinases-1 (TIMP-1) and also inhibits TNF-�, IL-1�, IL-12p40 and nitric oxide.[17]

Anticytokine therapies in various immune and inflammatory diseases
Regulation of the effects of cytokines has been suggested for therapeutics used in tissue destructive inflammatory diseases such as Rheumatoid arthritis (RA), Crohn�s disease, and various other immune and inflammatory diseases. Hence, inhibitors of cytokine production or action are widely investigated as potential therapeutic modalities in a variety of immune and inflammatory diseases including periodontitis.[8, 15, 18]

Strategies to inhibit cytokine activity [5, 10, 19]
Antibodies to specific cytokines
Immunoadhesins (recombinant soluble receptors)
Soluble cytokine receptors
Blockade of cytokine receptors
Disruption of cell signaling pathways or  activation of anti-inflammatory pathway  

Antibodies to specific cytokines are a leading approach to neutralize cytokines in the use of specific antibodies directed against the cytokine or its corresponding receptor. The advantages of this include are excellent solubility, exquisite specificity and long half-life in serum. It has certain limitations due to quick metabolism of antibodies and necessitates repeated administration. Administration of cytokine receptor antagonists can induce an antibody and neutralize cytokine and it eliminates the need for repeated administration of anticytokine antibodies.[ 4, 18-20] Example: IL-6 receptor antagonist.
Immunoadhesins are another approach used to develop biological inhibitors of cytokine activity to engineer a fusion protein that combines the constant domain of an antibody molecule with the ligand recognition domain of a cytokine receptor. Its advantages are that, it eliminates the need to immunize an animal, circumvent screening for cytokine specific antibodies, antigen recognition and extended half-life in serum. [14-16, 19]  
Soluble cytokine receptors are other means for regulating cytokine induced pathways. Cytokines produced during inflammation are strongly regulated at transcriptional and translational levels. Production of soluble cytokine binding receptors blocks cytokine action (except for IL-6) at the inflammatory site by downregulation mechanisms. These are found in blood and extracellular fluid and are derived from the proteolytic cleavage of the extracellular domains of cell membrane bound cytokine receptors. They downregulate the respective cytokines by blocking the signaling pathways. [4, 7, 10, 13, 14, 19]
Table 3: Cytokines and it�s agonists and antagonists [4, 7, 12, 16]
CytokinesAgonist
AntagonistIL-1�IL-1RI
IL-1RII
IL-1RAcPsIL-1R

IL-1RaTNF-�TNF-RI
TNF-RIIsTNF-RI
sTNF-RII
Anti   TNF antibodyIL-6IL-6R
(gp-130)
sIL-6RAnti-IL-6 antibody
sgp 130
Blockade of cytokine receptors[4, 7, 10, 13- 15, 19]
Natural cytokine receptor antagonists bind to the membrane receptors present on target cell and prevent respective cytokine binding to the target cell thereby preventing activation of the target cells. For example IL-1Ra (Inlerleukin-1 receptor antagonists) bind to IL-1RI but not to the     IL-1R associated proteins; it can bind to the IL-1RI with high affinity without activating signaling pathways and competitively blocks the IL-1 binding.

Disruption of cell signaling pathways or activation of anti-inflammatory pathway[20]
Pharmacological inhibitors of MAPK, NFkB, and JAK/STAT pathways are being developed to treat RA, periodontal diseases and other inflammatory diseases. 









Table 4: Various commercially available anticytokine drugs, it�s strategies to inhibit cytokine and targeted cytokine molecules [19, 21]
Type of strategy to inhibit cytokine activityCytokine antagonistsTarget cytokineBiological typeClinical statusAntibodies to specific cytokines
Infliximab� -Remicade� [5, 6]


Golimumab� (CNTO 148) - Simpani�[22]

Cetrolizumab pegol� (CDP870) - Cimzia�[23]



Canakinumab� (ACZ885) - Ilaris�[24]

Tocilizumab (Atlizumab) - Actemra�and RoActemra�[25]

Bevacizumab - AvastinTM [26]


HuMax-IL-15/ AMG714[27]


Basiliximab - Simulect�[28]


Daclizimab - Zenapax�[29]

Secukinumab - AIN457[30]

Denosumab - XGEVA�[31]

Ustekinumab (CNTO 1275) - Stelara�[32]

TNF-�


TNF-�

TNF-�


IL-1�

IL-6 R

VEGF-A

IL-15

IL-2R �

IL-2R �

IL-17A

RANKL

IL-12 and 
IL-23Chimeric monoclonal antibody (mAb)



Human mAb

Human mAb


Humanized mAb

Humanized mAb

Humanized mAb

Human mAb

Chimeric IgG1 mAb

Humanized mAb

Human IgG1k mAb

Human mAb

Human mAbApproved


Approved

Phase III


Approved

Approved

Approved

Phase I/II

Approved

Approved

Phase IIIb

Approved

ApprovedImmunoadhesinsEtanerecept - Enbrel�[33]

Altrakincept - Nuvance�

Rilonacept (IL-1 Trap) - Arcalyst�[34]
TNF-�, LT- �

IL-4

IL-1
Receptor /IgG fusion protein

Receptor /IgG fusion protein


Dimeric fusion proteinApproved

Phase II

Approved
Cytokine antagonistsKineret - Anakinra[13]

D2E7-Adalimumab[35]IL-1 R

TNF-�Receptor antagonist


Human IgG1 mAbApproved

Phase IIIDisruption of cell signaling pathwaysRWJ 67657[36]
VX-745 (Vertex Pharmaceuticals)[37] 

SP600125[38]TNF-�, IL-6 and IL-8


TNF-�, 
Interferon - gamma, IL-6, COX-2 and MMPsp38 mitogen activated protein kinases inhibitors

c-jun N-terminal kinase pathway inhibitors

Phase I- Testing of drug on healthy volunteers for dose-ranging, with sub therapeutic, but with ascending doses; Phase II and III � testing of drug on patients to assess efficacy and safety at therapeutic doses, differs in terms of number of participants, 100-300, 1000-2000 respectively.

Table 5: Various anticytokine drugs and their indications [19]
DrugIndicationsAvastin�Advanced breast and colorectal cancerRemicade�Ankylosing spondylitis: 5mg/kg
Crohn�s disease: 5mg/kg
Psoriatic arthritis: 5mg/kg
Rheumatoid arthritis: 3mg/kg
Psoriasis: 5mg/kgEnbrel�Ankylosing spondylitis
Juvenile rheumatoid arthritis
Psoriatic arthritis
Rheumatoid arthritis
PsoriasisD2E7 and HuMax-IL-15�Rheumatoid arthritisKineret�Rheumatoid arthritisSimulect� and Zenapax�Acute kidney transplantation rejectionNuvance�Asthma

Implications in Periodontal Diseases
Rheumatoid arthritis (RA) is one of the best disease models while describing the implications of anticytokine therapy. It has been noticed that RA resembles periodontitis with respect to pathogenesis, progression of disease and cytokine levels except IL-1�.[11] Therefore anticytokine therapy has been implicated in the treatment of experimental periodontitis.[12-15, 39]
Anticytokine therapy for periodontal diseases primarily targets production or actions of IL-1 �, IL-6, TNF-�, because they are necessary for the initiation and progression of periodontal diseases and persistent production at the inflammatory site. There exists a convincing evidence that inflammation associated with gingivitis is actively protective, since blocking further           upregulation of the host response with IL-1/TNF antagonists inhibits the inflammatory response and bone loss in periodontitis.[14] It has been shown that these utilization of soluble receptors, specific to inflammatory cytokines, which potentially stimulate fibroblasts to regulate biological events involved in the pathogenesis of periodontal diseases.[7] The loss of connective tissue attachment and progression of periodontal diseases can be retarded by soluble antagonist to specific host mediators such as IL-1 and TNF and may provide a potential treatment modality to combat the disease process.[16]
Treatment strategies currently available for controlling inflammation/bone resorption in periodontal diseases are:
Natural cytokine antagonists [4]
Neutralizing antibody to TNF-�: Infliximab� [5, 6]
Recombinant soluble receptor to TNF-�: Etanercept� [32]
Soluble human rhIL-1R type I[14]
Antagonist to IL-1R: Anakinra� [13]
Recombinant human IL-11 [17]
Cytokine suppressive anti-inflammatory drugs[36-38, 40]
Gene therapeutics [7]

Natural cytokine antagonists
It binds to the membrane receptors present on the target cell and prevent respective cytokine binding to the target cell thereby preventing activation of target cells. For example: IL-1Ra (Inlerleukin-1 receptor antagonists) bind to IL-1RI but not to the IL-1R associated proteins; it can binds to the IL-1RI with high affinity without activating signaling pathways and competitively blocks the IL-1 binding.[4]
Neutralizing antibody to TNF-�: Infliximab"! -Remicade� [5, 6, 41]
It is a chimeric IgG monoclonal antibody, which neutralizes pro-inflammatory cytokine, TNF-�. It has been shown in various studies that, periodontitis presents heaps similarities with RA with respect to TNF-� induced bone resorption, the benefits of TNF-a blockade in RA prompted to determine Infliximab efficacy in treating coexisting periodontitis. Patients with RA receiving Infliximab had lower periodontal indices and gingival crevicular fluid TNF-alpha levels.[5. 6] The periodontal status was evaluated in 40 subjects with RA who were divided into two groups: Group I contained 20 subjects who had received infliximab every 6 weeks for 22 months. The 20 subjects in group II were evaluated before their infusion with infliximab. Nine subjects in group II had periodontitis. These subjects were reassessed after they received nine infusions of infliximab. Results revealed that, although bacterial infection persisted, the probing depth was equal in groups I and II and equivalent before and after treatment in subjects with periodontitis, whereas attachment loss was decreased after infliximab treatment.[6]
A study conducted on wistar rats showed that, periodontitis induction by passing a 3.0 nylon thread around the upper left second molar and experimental animals were either treated with intravenous infliximab (1, 5, 7, and 10 mg/kg) or saline solution 30 min before the periodontitis induction and were followed until they were sacrificed on the 11th day and then MMP-1/8, RANK, RANK-L, and OPG Gingival myeloperoxidase (MPO), IL-1�, TNF-� were measured by ELISA. It was found that Infliximab (5 mg/kg) reduced granulocyte blood counts, gingival IL-1�, TNF-�, and MPO levels, diminished MMP-1/8, RANK, and RANK-L in comparison with the control saline group. Thereby it was shown that infliximab had significant anti-inflammatory and bone-protective effects in Wistar rats induced by periodontitis.[41]
Recombinant soluble receptor to TNF-�: Etanercept (Enbrel)� [33]
Etanercept (75-kDa) is a dimeric, recombinant soluble form of the TNF-R consisting of extracellular domain of TNF-RII linked to the Fc portion of a human IgG1. The anti-inflammatory effects of etanercept are due to its ability to bind to TNF-�, preventing it from interacting with cell membrane bound receptors and making it into biologically inactive. Etanercept can also modify biological responses that are induced or regulated by TNF, including both expression of adhesion molecules responsible for leukocyte migration and serum levels of cytokines and matrix metalloproteinase-3.[32] Treatment of the rats with etanercept (5 mg kg_1, sub cutaneously, after placement of the ligature) significantly reduced the degree of periodontitis inflammation and tissue injury, infiltration of neutrophils, iNOS (the expression of nitrotyrosine and cytokines (eg TNF-a) and apoptosis (Bax and Bcl-2 expression). Therefore, it demonstrated that treatment with etanercept reduces the development of inflammation and tissue injury, events associated with periodontitis. [33]

Soluble human rhIL-1R
Soluble human rhIL-1R type I consisting of the extracellular portion of the type I receptor. It has been shown in various studies that function-blocking of soluble receptors to IL-1 were applied by local injection to sites (6.6 �g/injection three times each week for 6 weeks) in experimental animals with induced periodontitis inhibits approximately 80% the recruitment of inflammatory cells in close proximity to bone. The formation of osteoclasts was reduced by 67% at the experimental sites compared with that at the control sites (sites injected with vehicle alone), and the amount of bone loss was reduced by 60%.[14]
IL-1 and TNF antagonists significantly reduced the loss of connective tissue attachment by approximately 51%, and the loss of alveolar bone height by almost 91% both of which are statistically significant.[16] In periodontal research, the effects of soluble receptors and receptor antagonists of IL-1 and TNF- � have been studied during experimentally induced periodontitis in a non-human primate model.[15] 
The clinical, radiographic and biochemical findings of these experiments allowed that IL-1 and TNF-� antagonists blocked
the progression of the inflammatory cell infiltrate toward the alveolar bone crest
the recruitment of osteoclasts
periodontal attachment and bone loss
Compared with control animals, intra papillary injection of soluble receptor antagonists of IL-1 and TNF- � reduced the pattern of bone loss by approximately 50% as assessed by computer assisted densitometric Image analysis (CADIA).[15, 16]

Antagonist to IL-1R: Anakinra (Kineret)� [13]
It is an IL-1 receptor antagonist and blocks the biological activity of IL-1 by competitively inhibiting the binding of IL-1 to the cell membrane bound IL-1 receptor in both in vivo and in vitro and prevents cell signaling pathways and thereby renders inflammation and reduces tissue destruction in periodontal diseases.

Recombinant human IL-11 (rhIL-11)
 It inhibits TNF-� and other pro-inflammatory cytokines and stimulates TIMP-1 and minimizes inflammation and tissue destruction respectively. Subcutaneous administration of rhIL-11 twice a week had the ability to reduce the rate or extent of periodontal attachment loss and radiographic bone loss in a ligature induced beagle dog model after eight week period.[18]

Cytokine suppressive anti-inflammatory drugs[36-38, 40]
 Plaque accumulation at gingival margin can cause inflammatory cascade through series of signaling pathways which helps in recognizing external antigen. Signal travels through the cytoplasm and reaches the nucleus, and ultimately the pattern of gene expression is altered by transcriptional and post-transcriptional mechanisms. all cellular events in acquired and innate immunity depends on the activation of multiple signal transduction pathways, which may be affected by various factors both microbial- and host-derived, including lipopolysaccharide (LPS), proteases, cytokines and other enzymes. 
In periodontal diseases the most important pathways include the mitogen activated protein kinases (MAPK), nuclear factor kappa B (NF-kB), and Janus tyrosine kinase-signal transducer and activator of transcription (JAK/STAT). MAPKs are involved in signal transduction of extracellular hormones, growth factors, cytokines, bacterial antigens and environmental stresses and play a crucial role in many aspects of immune mediated inflammatory response. The three main sub-families of MAPKs are extracellular- regulated kinases (ERK-1/-2), c-Jun N-terminal activated kinases (JNK) and p38. Hence inhibition of these signaling pathways prevents tissue destruction and inflammation. Main drawbacks are lack of specificity and development of side effects. After overcoming these drawbacks, adjunctive host modulating drugs will provide new therapeutic strategies for periodontal treatment.



Table 5: Cytokine suppressive anti-inflammatory drugs[36-38, 40] targeted signaling pathways
Type of strategy to inhibit cytokine activityCytokine antagonistsTarget cytokineBiological typeDisruption of cell signaling pathwaysRWJ 67657[35]
VX-745 (Vertex Pharmaceuticals)[36] 

SP600125[37



SD-282]TNF-�, IL-6 and IL-8


TNF-�, 
Interferon - gamma, IL-6, COX-2 and MMPsp38 mitogen activated protein kinases inhibitors

c-jun N-terminal kinase pathway inhibitors



p38�MAPK mitogen activated protein kinases
It has been stated that administration of  SD-282 (15 or 45mg/kg) reduced LPS induced periodontal disease, inflammatory cytokine expression, osteoclastogenesis and alveolar bone loss in rat model by inhibiting p38�MAPK mitogen activated protein kinases inhibitors.[40]

Gene therapeutics
Human gingival fibroblasts (HGF) constitute the major cell population in periodontal tissues. If we could modify HGF activities, it can serve as secreting anticytokine and anti-microbial molecules. HGF deport as anti TNF-� system in periodontal tissue by secreting sTNF-RII antagonists for mTNF-Rs. Modified TNF-RII gene is introduced to gingival fibroblasts to overexpress sTNF-RII and this soluble form blocks binding of TNF-� to mTNF-Rs by binding TNF-� around gingival fibroblasts, It is seen that it has been suitable in the treatment of chronic infections and inflammations.[7]

Therapeutic strategies promising major breakthrough in medical and dental fields might also have a certain limitations. There is evidence of infections without inflammatory symptoms. To prevent this event, anti-microbial therapy can be considered for chemical plaque control in addition to scaling and root planing and it also down regulates the immune system, so increases the risk of microbial infection. Hence the screening of latent infectious diseases, such as tuberculosis, should be performed, and also with anti-microbial agents, caution must be taken to prevent apparent infection, without inflammatory symptoms when anticytokine therapy is performed.

Conclusion
Cytokines are known to play a key role in the pathogenesis of various inflammatory disorders. They appear to interact functionally in the periodontium and integrate the various aspects of innate and adaptive immunity. Anticytokine therapy can act as a host response modulator in the control of inflammatory diseases of periodontium and may provide the basis for new molecular therapeutic approaches in the treatment of periodontitis. In this era, where research has been focused on the molecular level of analysis, treatment should also be focused on eliminating the root cause. Therefore, further periodontal studies should be diverted towards the use of anticytokine therapy in the near future for better understanding and targeting the cellular and molecular pathways of periodontal disease pathogenesis.
References:
Roberts FA, Mc Caffrey KA, Michalk SM. Profile of cytokine m-RNA expression in chronic adult periodontitis. J Dent Res 1997;76:1833-1839.
Gemmell E, Seymour GJ. Immunoregulatory control of Th1/Th2 cytokine profiles in periodontal disease. Periodontology 2000 2004;35:21-41.
Gemmell E, Marshal R, Seymour G. Cytokines and prostaglandins in immune homeostasisand tissue destruction in periodontal disease. PeriodonroIogy 2000 1997;14:112-143.
Liu Y, Learner U, Teng Y. cytokine response against periodontal infection: protective and destructive roles periodontology 2000 2010;52:163-206.
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Mayer%20Y%5BAuthor%5D&cauthor=true&cauthor_uid=19722791" Mayer Y,� HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Balbir-Gurman%20A%5BAuthor%5D&cauthor=true&cauthor_uid=19722791" Balbir-Gurman A,�Machtei EE. Anti-tumor necrosis factor-alpha therapy and periodontal parameters in patients with rheumatoid arthritis. J Periodontol 2009;80:1414-1420.  
 HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Pers%20JO%5BAuthor%5D&cauthor=true&cauthor_uid=18771364" Pers JO,� HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Saraux%20A%5BAuthor%5D&cauthor=true&cauthor_uid=18771364" Saraux A,� HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Pierre%20R%5BAuthor%5D&cauthor=true&cauthor_uid=18771364" Pierre R,� HYPERLINK "http://www.ncbi.nlm.nih.gov/pubmed?term=Youinou%20P%5BAuthor%5D&cauthor=true&cauthor_uid=18771364" Youinou P. 23;<CI��6
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