|Year : 2016 | Volume
| Issue : 1 | Page : 12-16
Cytokines and Other Inflammatory Mediators in Periodontal Health and Disease
Harpreet Singh Grover, Rohit Saini, Pearl Bhardwaj, Amit Bhardwaj
Department of Periodontology, Faculty of Dental Sciences, SGT University, Gurgaon, Haryana, India
|Date of Web Publication||27-Jun-2016|
Department of Periodontology, Faculty of Dental Sciences, SGT University, Gurgaon, Haryana
Source of Support: None, Conflict of Interest: None
Cytokines and selective inflammatory mediators play crucial roles in the maintenance of tissue homeostasis. Growth factors such as fibroblast growth factor, platelet-derived growth factor, insulin-like growth factor, and transforming growth factor-β are thought to play important roles in modulating the proliferation and migration of structural cells in the periodontium. These biomolecules have a range of overlapping functions to help engage and control immune and inflammatory responses.
Keywords: Chemokines, fibroblast growth factor, insulin-like growth factor, platelet-derived growth factor, prostaglandins, transforming growth factor-β
|How to cite this article:|
Grover HS, Saini R, Bhardwaj P, Bhardwaj A. Cytokines and Other Inflammatory Mediators in Periodontal Health and Disease. Indian J Oral Health Res 2016;2:12-6
|How to cite this URL:|
Grover HS, Saini R, Bhardwaj P, Bhardwaj A. Cytokines and Other Inflammatory Mediators in Periodontal Health and Disease. Indian J Oral Health Res [serial online] 2016 [cited 2019 Jan 24];2:12-6. Available from: http://www.ijohr.org/text.asp?2016/2/1/12/184728
| Introduction|| |
Many biological events are strictly regulated by cell-cell interactions, which are categorized into two forms: cognate (adhesive) interactions, achieved by mutual recognition between membrane-bound cell-surface molecules and cytokine-mediated interactions.  Cytokines are soluble proteins that bind to specific receptors on target cells and initiate intracellular signaling cascades resulting in phenotypic changes in the cell via altered gene regulation. They are effective at low concentrations, are produced transiently in the tissues in which they are produced, induce their own expression in an autocrine or paracrine fashion, and have pleiotropic effects on a large number of cell types. 
Cytokines and selective inflammatory mediators play crucial roles in the maintenance of tissue homeostasis, a process which requires a delicate balance between anabolic and catabolic activities.  In particular, growth factors such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), and transforming growth factor-β (TGF-β) are thought to play important roles in modulating the proliferation and migration of structural cells in the periodontium and the production of various extracellular matrices by these cells. There is little doubt that excessive and continuous production of cytokines in inflamed periodontal tissues is responsible for the progress of periodontitis and periodontal tissue destruction. Particularly, inflammatory cytokines such as interleukin (IL)-lα, IL-β, IL-6, and IL-8 are present in the diseased periodontal tissues, and their unrestricted production seems to play a role in chronic leukocyte recruitment and tissue destruction.  The factors included in the cytokine molecule group are ILs, interferons, growth factors, cytotoxic factors, activating or inhibitory factors, colony stimulating factors, and intercrines.  As a rule, the synthesis of cytokines is inducible, although some factors are known to be produced constitutively. The mechanisms by which cytokines act on the target cells are classified into four types: autocrine, intracrine, juxtacrine, and paracrine.
| Cytokines and role in immunity|| |
The innate immune system serves as the first line of defense against an unknown antigen. A series of pro-inflammatory cytokines including IL-1α/β, IL-6, tumor necrosis factor-alpha (TNF-α), chemokines (IL-8), and interferons are synthesized de novo following bacterial or viral infections. These cytokines are active in stimulating phagocytic cells, monocytes, macrophages, neutrophils, and endothelial cells to react against or bind to microorganisms and other immune cells to the site of infection. 
| Role of cytokine expression in periodontal health and disease|| |
Tissue homeostasis represents a delicate balance between anabolic and catabolic activities.
Cytokine expression in periodontal health
Fibroblast growth factor
FGFs are one of the well-characterized cytokine families that can be found in many tissues. Two of the nine isoforms of FGF have been characterized in some detail: one is acidic FGF (aFGF; FGF-1) and the other is basic FGF (bFGF; FGF-2). Both FGFs bind to heparan sulfate, heparin, and fibronectin in the extracellular matrix. aFGF is primarily known for its effect on endothelial cell replication and neovascularization. Like aFGF, bFGF has angiogenic properties and is highly chemotactic and mitogenic for a variety of cell types. It stimulates bone cell replication and increases the number of cells of the osteoblastic lineage. FGF is a potent stimulator of periodontal ligament (PDL) cell migration and mitogenesis. 
Platelet-derived growth factor (AA, AB, BB)
PDGF, which was originally detected in the α-granules of platelets, is a potent growth factor for various connective tissue cells. A plethora of other cell types also synthesize PDGF including macrophages, endothelial cells, fibroblasts, astrocytes, myoblasts, and smooth-muscle cells. Platelets synthesize a mixture of the three possible isoforms (70% AB, 20% BB, and 10% AA), while epidermal growth factor (EGF)-stimulated fibroblasts synthesize AA homodimers. Activated macrophages and placental cytotrophoblasts produce the BB homodimer. The binding of PDGF to several plasma proteins and extracellular matrix facilitates local concentration of the factor. PDGF functions as a local autocrine and paracrine growth factor. PDGF is a powerful promoter of cell migration and proliferation. 
Insulin-like growth factors (I and II)
Two different IGFs (IGF-I and IGF-II) have been described.  Both were isolated initially as serum factors with insulin-like activities that could not be inhibited by anti-insulin antibodies. The structure of both IGFs is homologous to human pro-insulin. In periodontal research, it was shown that IGF-I is chemotactic and mitogenic for PDL cells. Although a single application of IGF-I only slightly induces periodontal tissue regeneration, several lines of evidence suggest that IGF-I combined with other growth factors such as bFGF, PDGF, and TGF-3 may augment the osseous wound-healing process. 
Transforming growth factor-b
TGF-β appears to be synthesized by all normal cells studied to date. The different isoforms of TGF-β (TGF-β1, TGF-β2, and TGF-β3) are encoded by different genes. TGF-β is the most potent known growth inhibitor for epithelial cells, endothelial cells, fibroblasts, neuronal cells, lymphocytes, and hepatocytes. It stimulates the synthesis of connective tissue matrix components, such as collagen, fibronectin, proteoglycan, glycosaminoglycan, osteonectin, and osteopontin in many cell types, including PDL cells.  It also inhibits the degradation of matrix proteins by inhibiting the synthesis of metalloproteinases such as collagenase and by increasing the synthesis of proteinase inhibitors. 
Cementum-derived growth factor
Cementum-derived growth factor (CGF) was detected exclusively in cementum and was shown to be the major cementum mitogen for PDL cells and gingival fibroblasts. It has been suggested that CGF may promote the migration and growth of progenitor cells present in structures adjacent to the dentin matrix and participate in their differentiation into cementoblasts. 
Cytokine expression in periodontal disease
Two of the most important proinflammatory cytokines are IL-1 and TNF-α. Offenbacher in 1996 suggested that if the antibody/neutrophil response does not result in clearance, the outcome of monocyte/lymphocyte challenge is the secretion of catabolic cytokine and inflammatory mediator, which induce connective tissue and bone loss.
There are three IL-1 ligands, IL-1β, IL-α, and IL-1 receptor antagonist (IL-1ra). IL-1α and IL-1β have similar biological activity, while IL-1ra binds to IL-1 receptors, but does not have agonist activity and acts as a competitive inhibitor.  IL-1 was discovered by Gery et al. in 1972 and was described as a lymphocyte-activating factor based on its mitogenic activity on lymphocytes. These biomolecules have a range of overlapping functions to help engage and control immune and inflammatory responses.  Following activation, it is synthesized by various cell types, including macrophages, monocytes, lymphocytes, vascular cells, brain cells, skin cells, and fibroblasts. IL-1α and IL-1β share only 27% homology at the amino acid level, but they have similar biological functions. It has been demonstrated that IL-lα remains largely cell-associated, whereas IL-1β is released from the cell.
IL-1 is known to stimulate the proliferation of keratinocytes, fibroblasts, and endothelial cells and to enhance fibroblast synthesis of type I procollagen, collagenase, hyaluronate, fibronectin, and prostaglandin E2 (PGE2). The local excessive production of IL-I by cells composing the periodontium appears to be capable of stimulating gingival and PDL fibroblasts, in an autocrine or paracrine fashion, to induce the production of other cytokines, matrix-degrading enzymes, and PGE2. These mediators may be responsible for effecting connective tissue destruction, leading to the loss of attachment. Thus, IL-1 has been suggested to play a key role in promoting alveolar bone destruction in periodontal disease.  There is evidence that susceptibility to periodontal disease is influenced by genetic polymorphism of IL-1 gene. Some studies report on an association between IL-1 and severity of periodontal disease genotype.  In a meta-analysis, it is demonstrated that IL-1α and IL-1β genetic variation are significant contributors to chronic periodontitis. 
It has pro-inflammatory properties, plays a key role in acute inflammation, and promotes bone resorption. It also stimulates T-cell differentiation.  IL-6 is clearly an IL that mediates communication between a large number of cell types by playing a role in the proliferation and differentiation of B-lymphocytes, hematopoietic progenitors, hepatocytes, and T-lymphocytes.  IL-6 is also one of the cytokines found in gingival crevicular fluid (GCF) of patients with refractory periodontitis, who are undergoing active bone loss.  In this way, IL-6 which is a pro-inflammatory cytokine contributed to periodontitis-induced bone resorption.
Formerly known as neutrophil-activating peptide-1, it is a potent chemotactic factor for leukocytes. IL-8 is secreted by a variety of cells, including monocytes, fibroblasts, lymphocytes, and endothelial cells.  In inflamed gingival tissue, it is expressed in epithelial cells and macrophages. It may play a significant role in the pathogenesis of periodontitis. It is likely that locally secreted IL-8 induces neutrophil extravasation at the site of inflammation, and numerous neutrophils present in lamina propria and epithelium of inflamed gingiva may be detected by IL-8.
These cells are termed as "Th-17." IL-17 has been shown to stimulate epithelial, endothelial, and fibroblastic cells to produce IL-6, IL-8, and PGE2. It induces the receptor activator of nuclear factor-kappa β ligand (RANKL) production of osteoblasts and influence osteoblastic bone resorption.  IL-17 mediated inflammation in the initiation and progression of periodontal disease suggesting that Th-17 cells may contribute to pathogenic tissue destruction that occurs in periodontal disease. IL-17 seems to blur the lines between innate and adaptive immunity because it is secreted byadaptive immune system and it mediates the activation of products typical of innate inflammatory effects such as TNF-α and IL-1β. IL-17 can modulate the RANKL/osteoprotegerin (OPG) ratio and increases RANKL expression and concomitantly decreases OPG expression in osteoblastic cells. 
Lymphokine expression by T-cells in periodontal disease
T-cells play a crucial role in regulating a variety of immune responses by secreting various cytokine, formerly known as lymphokine.
Tumor necrosis factor-alpha
TNF refers to two associated proteins, TNF-α and TNF-β. There are two structurally similar TNF cell surface receptors, TNF receptor-1 (TNFR-1) and TNF receptor-2 (TNFR-2). These receptors activate different signaling pathways and have different cytoplasmic domains. Most of the inflammatory effects are mediated through TNFR-1 signaling, while TNFR-2 attenuates the inflammatory response induced by TNF.  TNF-α is a pro-inflammatory cytokine that is secreted mainly by monocytes and macrophages. It induces the secretion of collagenase by fibroblasts, resorption of cartilage and bone, and has been implicated in the destruction of periodontal tissue in periodontitis. It also activates osteoclasts and thus induces bone resorption. 
It is a lymphokine produced by activated T-lymphocytes and natural killer cells that plays an important role in host defense mechanisms by exerting pleiotropic activities on a wide range of cell types. Cellular responses to interferon-gamma (INF-g) are mediated by its heterodimeric cell surface receptor (IFN-gR), which activates downstream signal transduction cascades, ultimately leading to the regulation of gene expression. As an inflammatory cytokine, INF-g was studied as a mediator of periodontal destruction in animal and human studies. 
Receptor activator of nuclear factor-kappa B ligand-receptor activator of nuclear factor-kappa β-osteoprotegerin axis
RANK, RANKL, and OPG are cytokines that belong to TNF-α super family. RANK is a receptor found on the surface of osteoclast precursors. When RANK binds to its ligand RANKL, it stimulates the differentiation of these precursor cells into mature osteoclasts. OPG competes with RANKL by binding to RANK without stimulating any differentiation. It is the ratio of RANKL and OPG expressions that is important in inflammation-induced bone resorption, including periodontitis. 
| Role of receptor activator of nuclear factor-kappa beta/osteoprotegerin in periodontal disease|| |
Bone resorption and formation are regulated by the relative concentrations of RANKL, RANKL receptor RANK on osteoclast precursor cells, and the soluble decoy receptor OPG. When RANKL expression is enhanced relative to OPG, RANKL is available to bind to RANK on osteoclast precursors, tipping the balance to favor the activation of osteoclast formation and bone resorption. The binding of RANKL to osteoclast precursors occurs at a stage when hematopoietic stem cells have differentiated from the colony forming unit (CFU) for granulocytes and macrophages to the CFU for macrophages (CFU-M). Binding of RANKL to RANK on CFU-M in the presence of macrophage colony stimulating factor induces differentiation of preosteoclast into a multinucleated cell that becomes a mature osteoclast, which then resorbs bone. When OPG concentrations are high relative to RANKL expression, OPG binds RANKL, inhibiting it to bind to RANK. Preventing the binding of RANKL to RANK leads to reduced formation of osteoclasts and apoptosis of pre-existing osteoclasts. 
| Role of cytokines in bone uncoupling|| |
Bone is resorbed by osteoclasts, following which new bone is laid down by osteoblasts in the resorption lacunae. Under physiologic conditions, the two activities are coupled, i.e., the amount of bone formed by osteoblasts is equal to that resorbed by osteoclasts. In pathologic processes such as periodontal disease and osteoporosis, the two processes are uncoupled, i.e., there is deficient bone formation following resorption.
The inflammatory process that leads to osteoclastogenesis and bone resorption may also be responsible for the failure to form adequate amount of new bone, i.e., inflammation causes uncoupling of bone formation following bone resorption. Osteoblast survival is a key factor in bone formation. TNF-α stimulates the production of Dickkopf-1 (DKK-1), which suppresses bone formation by inhibiting the WNT (wingless WNT/beta catenin) pathway. DKK-1, a negative regulator of WNT pathway, is up-regulated by TNF stimulation through TNF-1 receptor and p38 mitogen-activating protein kinase signaling. The up-regulated DKK-1 not only promotes bone resorption but also blocks bone formation and repair in the diseased joint. Thus, inflammatory cytokines such as TNF-α can limit bone formation by inhibiting osteoblast differentiation. In addition, the pro-inflammatory cytokines may directly stimulate osteoblast or osteoblast precursor indirectly affect by stimulating expression of Fas, a potent apoptotic mediator. PDL cells are an important source of osteoblast precursors. TNF-α-induced apoptosis of PDL cells may affect the pool of osteoblast precursors.
Another mechanism for uncoupling is the reduced function of osteoblasts mediated by diminished production of bone matrix proteins. TNF-α and TNF-β induce a 2-fold to 3-fold reduction in synthesis of noncollagen bone matrix proteins such as osteocalcin by osteoblasts. TNF-specific inhibitor, etanercept, promotes bone morphogenic protein-2-induced ectopic bone formation when applied systemically or locally in vivo, thereby improving the coupling process. 
| Chemokines in periodontal disease|| |
Chemokines are a class of chemotactic cytokines that stimulate recruitment of relatively specific leukocytes subsets. They are secondary inflammatory mediators that are induced by external signals such as IL-1 or TNF-α, growth factors, and viral and bacterial infection or their products.  Chemokines are divided into four sub-families based on molecular structure (CXC, CX3C, CC, and C). The nomenclature has been revised according to the receptor nomenclature (CCL1, CXCL1, etc.). They are named by position of two cysteine residues compared with other amino acids. Chemokines are produced by various resident and infiltrating cells (fibroblasts, osteoblasts, mast cells, epithelial cells, and endothelial cells), they play a key role in inflammation by orchestrating the tissue distribution of leukocyte subsets in tissues and regulating cell migration and proliferation.
Activation of signaling pathways by chemokine receptor binding results in reorganization of the cell cytoskeleton, resulting in pseudopodia which permit the cell to move up the chemotactic gradient.  Chemokines that cause recruitment of leukocytes are termed as inflammatory. In persons with periodontitis, the level of IL-8/CXCL8 in both periodontal tissue and GCF is drastically increased and has been correlated with disease severity.  Another chemokine that contribute to the enhanced severity of periodontal disease is MCP-1, which is supposed to be a major chemoattractant of macrophages in periodontal disease. MCP-1 activity in GCF is increased in the severity of disease.  One of the most abundantly expressed chemokines in periodontitis tissue is macrophage inflammatory protein 1, with expression localized in the connective tissue subjacent to pocket epithelium of inflamed gingival tissues.  Chemokines can also exert important effects on bone cells inducing the migration and activation of osteoclasts. In addition, stromal cell derived factor-1 is a positive regulator of osteoclast function and recently identified as diseased periodontium. 
| Prostaglandins in periodontal disease|| |
PGs are derived from the hydrolysis of membrane phospholipids. Phospholipase A2 cleaves the sn-2 position of membrane phospholipids to free arachidonic acid, a precursor of a group of small lipids known as eicosanoids. Arachidonic acid is metabolized by two major enzyme pathways. Lipoxygenases (LO) catalyse the formation of hydroxyeicosatetraenoic acids leading to the formation of leukotrienes (LTs). Cyclooxygenases (COX-1 and COX-2) catalyse the conversion of arachidonic acid into PGs prostacyclins and thromboxanes.  COX-1 is a constitutive enzyme responsible for the formation of PGs with physiological functions, while COX-2 is an inductive enzyme induced primarily by proinflammatory cytokines and leads to the formation of PGs involved in pathophysiological processes such as edema formation and fever.
PGs have 10 sub-classes, of which D, E, F G, H, and I are the most important in inflammation. They are potent stimulators of bone formation and resorption and are produced by osteoblasts and PDL cells. They also have inhibitory effects on fully differentiated osteoblasts and osteoclasts.  PGE2 is a potent stimulator of alveolar bone resorption. PDL cells also produce PGE2 even when unstimulated. This secretion is enhanced by IL-1b, TNF-α, and LO. COX products (LTB4, thromboxanes, and PGE2, respectively) play important roles in systemic inflammation, endothelial cell activation, vascular EGF expression, and platelet aggregation. 
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Conflicts of interest
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