Department of periodontology, Faculty of Dentistry, University of Khartoum, Sudan
Received: 27 April, 2016; Accepted: 03 May, 2016; Published: 04 May, 2016
Nada Tawfig, Assistant Professor, Department of Periodontology, Faculty of Dentistry, University of Khartoum, Sudan, E-mail:
Tawfig N (2016) Proinflammatory Cytokines and Periodontal Disease. J Dent Probl Solut 3(1): 012-017. 10.17352/2394-8418.000026
© 2016 Tawfig N. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Numerous biological procedures are strictly controlled by cell-cell interactions, which are categorized into two forms: cognate (adhesive) interactions, attained by mutual recognition between membrane-bound cell-surface molecules; and cytokine-mediated interactions .
Cytokines (Greek cyto-, cell; and -kinos, movement) are a category of signaling molecules that are used extensively in cellular communication.
The responses caused by these substances are diverse and interrelated. Generally, cytokines control growth, mobility and differentiation of lymphocytes, but they also exert a similar effect on other leukocytes and some non-immune cells .
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B lymphocytes, T lymphocytes and mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cells. They used to have different names depending either on their origin, such as lymphokines (produced by lymphocytes), monokines (monocytes) or on their activity: chemokines, interleukins, interferon. The term “cytokine” has been used to refer to the immunomodulating agents, such as interleukins and interferons [3-5].
After binding with high affinity to specific receptors on target cells cytokines are capable of regulating pluripotent activities such as: cellular growth, differentiation, proliferation, migration, angiogenesis and fibrosis as well as apoptosis of the multiple cell types. Furthermore they are able to regulate the specific immune responses .
Some cytokines enhance or stop the action of other cytokines in complex ways, while others are chemical switches that turn certain immune cell types on and off. They include a diverse assortment of interleukins, interferons, and growth factors. They are important in health and disease, specifically in host responses to infection, immune responses, inflammation, trauma, sepsis, cancer, and reproduction .
Pro-inflammatory cytokines and chemokines, comprising IL-1, IL-6, IL-8, and TNF-alpha create an environment that helps disease progression. These cytokines and chemo attractants are secreted by immune regulatory cells, tumor cells, tumor-associated macrophages, and stromal cells .
Cytokine expression in periodontal health
Tissue homeostasis denotes 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 cytokines, which are secreted by fibroblasts endothelial cells, and epithelial cells, have a key role in tissue homeostasis .
There are at least two major pathways that control the balance of gingival tissue and bone remodeling and the subsequent control of periodontal bone loss. The first encompasses the interactions with osteoblasts and stroma that couple between bone formation and resorption during physiological bone remodeling processes. Through the network of autocrine and paracrine regulations, a range of growth factors, such as platelet derived growth factor, basic fibroblast growth factor and insulin-like growth factor, exert their activities through their receptors on osteoblasts to stimulate the formation of new bone .
The second pathway deals with the inflammatory or ⁄ and osteoclastogenic cytokines ⁄ mediators that are produced during local tissue inflammation and trauma or systemic assaults and are thus responsible for bone loss under pathological conditions where bone remodeling becomes imbalanced or dysregulated as a result of increased osteoclast number and activity, resulting in irreversible bone loss .
The epithelium in the gingiva consists mainly of keratinocytes, but other cells are also present, including Langerhans cells, T-cells, Merckel cells and melanocytes keratinocytes in the gingival epithelium are continuously proliferating and gingival epithelium is well differentiated in morphologically distinguishable cell layers.
Although the epithelium was originally considered to be a physical barrier that protected the host from bacterial invasion, we now know that it plays a much more active role in the pathogenesis of inflammation .
Keratinocytes can produce alpha- and beta-defensins, which are antimicrobial peptides that are involved in the host response against infection. Additionally, keratinocytes, when challenged with bacterial infection, express a large variety of cytokines and growth factors, including interleukin-1alpha, interleukin- 1beta, interleukin-8, tumor necrosis factor-alpha and platelet-derived growth factor. Physiologically, keratinocytes have a high turnover rate and, during inflammation the induction of epidermal growth factor enhances further proliferation. Together with cytokines and growth factors keratinocytes are able to express several adhesion molecules and integrins that serve as guidance receptors for leukocyte trafficking .
Connective tissue of gingiva and periodontal ligament
The extracellular matrix in the subepithelial gingiva and periodontal ligament is composed predominantly of type-I collagen fibers, with type-III, -IV, -V and –VI collagen fibers being present in lesser amounts .
Large and small proteoglycans, such as aggrecan, decorin, biglycan, syndecan, perlecan and versican, have been revealed in the gingiva. Additionally, fibronectin, osteonectin and vitronection are part of the extracellular matrix. The principal cell types are fibroblasts in the gingiva and fibroblast-like cells in the periodontal ligament. These cells express a variety of membrane and intracellular receptors, making the cells sensitive to regulation by many physiological and pathological, paracrine and endocrine signaling molecules .
Fibroblasts are the mesenchymal cells that secrete the extracellular matrix molecules. On the other hand, fibroblasts are also important for the remodeling of these molecules. To retain tissue homeostasis physiologically, the degradation and the synthesis of these molecules have to be well controlled .
Platelet derived growth factor, released from platelets, macrophages or gingival epithelium, is strong stimulators of fibroblast proliferation and are proposed to be important in inflammation-induced fibroblast proliferation.
Regulation of matrix molecules may occur either through increased or decreased biosynthesis, or enhanced or decreased enzymatic breakdown.
Transforming growth factor-beta, released from platelets or macrophages, activates the transcription of a number of the collagen genes for collagen synthesis besides inhibits the synthesis of matrix metalloproteinases. By contrast, prostaglandin E2, inteferon-gamma and tumor necrosis factor-alpha inhibit collagen synthesis. Interleukin-1 is a most effective regulator of extracellular matrix turnover by increasing the expression of several matrix metalloproteinases .
Alveolar bone tissue
The jaw bones are constituted of cortical bone in the periphery, including the tooth socket. In the central part of the mandible and maxilla, a relatively large amount of trabecular (spongious) bone is present, and bone marrow is distributed in between the trabecular bone. Histologically, there are large differences between cortical and trabecular bone, since the former is built up by lamellar bone surrounding Harversian canals harbouring blood vessels and nerves.
In addition to osteoblasts, bone tissue contains osteocytes. These cells are present within the mineralized bone and were originally osteoblasts, which were incorporated into the extracellular matrix and ultimately into the mineralized bone tissue. A third main cell is the osteoclast, the only cell that is capable of degrading bone, a process important for the remodeling and modeling of bone .
Bone tissue contains large amounts of growth factors, including transforming growth factor-beta, insulin-like growth factors I and II, basic fibroblast growth factor and bone morphogenetic proteins. These matrix molecules are mitogenic for osteoblasts and can also stimulate the bone-forming activity of osteoblasts. It is believed that these growth factors function during bone remodeling (when they are released during the resorptive process) and then act locally on osteoblasts. It is obvious that the amount of bone in the skeleton, including jaw bones, is regulated by many different signals. The number of osteoblasts present is dependent on osteoblast precursors differentiated from Mesenchymal stem cells, in a program where there is competition with differentiation along other pathways to adipocytes and related mesenchymal cells. The number of osteoblasts is then also dependent on signals controlling proliferation and apoptosis [11,16].
Pathogenesis of periodontal disease
Periodontal disease is one of the most prevalent diseases worldwide and includes two major conditions, gingivitis and periodontitis. The milder, reversible form of the disease, gingivitis, involves inflammation of the gingival tissue. In disease-susceptible individuals, gingivitis may progress to periodontitis, which is a chronic infectious disease of the supporting tissues of the teeth .
Although periodontal diseases are initiated by bacteria, the host response is believed to play an essential role in the breakdown of connective tissue and bone. Microbial antigens and virulence factors elicit an inflammatory and immune reaction, in which both innate and adaptive immune responses are, involved .
The response differs among individuals, depending on potential variations in cytokine and other antimicrobial responses, environmental factors, and the subjects’ genetics make up.
The host response to the bacterial challenge includes the action and stimulation of various inflammatory cell types as well as of resident cells of the tissue [19,20]. Antigens and products, such as LPS and peptidoglycans, released by bacteria are recognized by toll-like receptors (TLRs) on the surface of host cells, which initiates an inflammatory response .
Through a cascade of events, mast cells are stimulated to release vasoactive amines and preformed tumor necrosis factor α (TNFα), which increases vascular permeability and the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and P-selection on endothelial cell surfaces. This process recruits PMNs into the tissue, where they release lysosomal enzymes, which contribute to tissue degradation . In reaction, lymphocytes and macrophages further invade the tissue. 60−70% of the collagen in the gingival connective tissue is degraded at the site of the lesion at this point, however the bone is still intact .
At this stage, the gingival tissues damage is still reversible and it is possible to repair and remodel the damaged tissue after removal of the insult. However, in some individuals, due to innate susceptibility and/or environmental factors, the inflammation fails to resolve, with subsequent connective tissue breakdown and irreversible bone loss. In this situation, macrophages form pre-osteoclasts which, after maturing into osteoclasts, are capable of degrading alveolar bone .
Without active resolution of inflammation, the bacterial antigens ultimately encounter antigen presenting cells for instance dendritic cells, macrophages and B cells. Upon interaction of naïve CD4 T helper cells (Th0) with antigen presenting cells, naïve T cells differentiate into various subsets of cells including Th1, Th2, Th17 and regulatory T cells (Tregs), and this differentiation depends on the cytokines that they produce Figure 1.
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