Review article

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Cytokines and Oral Pathology – An Intricate Liason

Sneha Sethi, Pratul Aggarwal¹

Department of Oral Pathology, Sudha Rustagi College of Dental Sciences and Research, Faridabad, Haryana, India, ¹ Department of Conservative Dentistry and Endodontics, Private Practitioner, Jalandhar, Punjab, India.

Address for Correspondence:

Dr. Sneha Sethi, Senior Lecturer, Department of Oral Pathology, Sudha Rustagi College of Dental Sciences and Research, Faridabad, Haryana, India. Email:

[email protected]

ABSTRACT:

Cytokines are also referred to as bioactive cell secretions or messenger molecules of the immune system and are used extensively in intercellular communication. The cytokine system known to be involved in several biological responses and reactions in the human body is a multifarious and vibrant system,. An understanding of these biomessenger molecules and their biology is overwhelming and intimidating; it has its roots firmly adherent to the pathophysiologic processes and their possible treatment protocols. A few basic oral diseases like oral lichen planus, oral submucous fibrosis, gingival and periodontal inflammation owe their complex pathogenesis, outcome and course of disease to these multifaceted biomolecules. A helpful insight into cytokines has been included in this article, with stress on their involvement in oral diseases.

Keywords: cytokines, inflammation, lichen planus, orthodontics

INTRODUCTION:

Cytokines (Greek cyto-, cell; and -kinos, movement) are small cell-signaling protein molecules belonging to a family of glycosylated or non-glycosylated polypeptides and proteins, secreted by numerous cells in response to a stimulus.

They are also referred to as bioactive cell secretions or messenger molecules of the immune system and are used extensively in intercellular communication.^1,2 Owing to the numerous varied regulatory functions of these secretory molecules there is a noted widespread production by various cell types in several body sites (Table 1). There are many classifications

which have been proposed to categorize cytokines and a compilation of a few have been tabulated in Table 2. Specific receptors are present on the membranes of target cells, these are the potential sites through which cytokines exert their biological action. All receptors have at least one extracellular domain, a membrane spanning domain, and a cytoplasmic tail; the receptors have been divided into different groups according to activities and mechanisms.^3,4 Type I cytokine receptors include the mediators of hematopoiesis like GM-CSF, erythopoeitin; type II cytokine receptors include mediators of innate immunity like

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chemotaxis, activation, proliferation, differentiation and death of T- and B- lymphocytes.⁵

The intrinsic role of cytokines in the pathogenesis of diseases has been explored in great detail in previous studies and has

had a great impact on the molecular pathway involved and many potential therapeutic applications. This particular review highlights the significance of cytokines in oral physiological and pathological processes.

Table 1: Production of cytokines

SNO. CELL CYTOKINES PRODUCED

1. FIBROBLASTS EPIDERMAL GROWTH FACTOR, FIBROBLASTIC GROWTH FACTOR, INTERFERONS, INTERLEUKINS, NERVE GROWTH FACTOR, PLATELET DERIVED GROWTH FACTORS

2. MACROPHAGES INTERLEUKINS, NERVE GROWTH FACTOR

3. T-CELLS INTERFERONS, INTERLEUKINS, NERVE GROWTH FACTOR, THROMBOPOEITIN

4. BONE-MARROW STROMAL CELLS

HEMATOPOIETIC GROWTH FACTORS

5. NEUTROPHILS HEMATOPOIETIC GROWTH FACTORS 6. NATURAL KILLER CELLS INTERFERONS, INTERLEUKINS 7. BASOPHILS HEMATOPOIETIC GROWTH FACTORS

8. EOSINOPHILS HEMATOPOIETIC GROWTH FACTORS, THROMBOPOEITIN

9. ENDOTHELIAL CELLS FIBROBLASTIC GROWTH FACTOR, PLATELET DERIVED GROWTH FACTORS

10. KIDNEY CELLS ERYTHROPOIETIN

11. LIVER CELLS ERYTHROPOIETIN, HEMATOPOIETIC GROWTH FACTORS, INSULIN GROWTH FACTORS

Cytokines in inflammation

Inflammation has been broadly categorized as acute and chronic, and IL-1, TNF- α, IL-6, IL-11, IL-8, G-CSF, and GM-CSF are known to play a role in the acute type;

whereas chronic inflammation is of two types⁶

1) humoral type mediated by IL-4, IL-5, IL-6, IL-7, and IL-13, and

2) cellular type mediated by -1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferons, TGF-β, and TNF - α and β.

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respect to inflammation, i.e. pro-

inflammatory and anti-inflammatory cytokines (Table 3).

Table 2: Classification of cytokines

SNO. CLASSES REFERENCE

1.

On the basis on mechanism of action:

- Autocrine - Intracrine - Juxtacrine - Paracrine

Idelgaufts (1995)³

2. On the basis of cell types producing factors 1. Growth Factors:

a. Haemopoietic Growth Factor: Granulocytes- Colony Stimulating Factor (G-CSF), Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF), Macrophage Colony- Stimulating Factor, Erythropoietin (EPO), Thrombopoietin, Stem Cell Factor or c-kit ligand

b. Epidermal Growth Factor c. Platelet Derived Growth Factor d. Transforming Growth Factor Beta e. Fibroblast Growth Factor

f. Insulin-like Growth Factor g. Nerve Growth Factor

2. Interleukins: IL-1, IL-2, 3, IL-8 etc.

3. Interferon: IFN-α, IFN-, IFN-γ.

4. Miscellaneous

5. Tumor Necrosis Factor (TNF) etc.

Ikram N et al (2004)²

3. On the basis of their general properties:

1. Cytokines involved in the activation of cells of the immune system.

2. Cytokines involved in hematopoiesis

3. Cytokines that contribute to inflammatory processes.

4. Cytokines involved in cytostatic, cytotoxic and antiviral activities.

Ikram N(2004)²

4. On the basis of their functions:

1. Cytokines of innate immunity.

2. Cytokines of adaptive immune responses 3. Cytokines stimulating hematopoiesis

Cotran, Kumar and Collins⁴

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Pro-Inflammatory Cytokines

IL-1β monocytes, macrophages, fibroblasts, endothelial cells, nociceptive neurons

TNF-α macrophages, CD4+

lymphocytes, Natural Killer cells, neutrophils, mast cells, eosinophils and neurons

Anti-Inflammatory Cytokines

IL-1 macrophages, neutrophils, epithelial cells, endothelial cells, Langerhans cells, natural killer cells

IL-4 CD-4 cells

1L-10 activated macrophages and by helper T cells

IL-11 megakaryocytes, epithelial cells, adipocytes

IL-13 T-Helper cells

Both Pro- And Anti-Inflammatory Cytokines

IFN- α natural killer cells, macrophages, fibroblasts, monocytes, T-helper cells,

TGF-β macrophages, T-cells

IL-6 monocytes, T-lymphocytes, tissue macrophages, fibroblasts, microglia, astrocytes, cells of pituitary gland.

Inflammatory reactions and sites are a swarming cocktail of cytokines and their effects; numerous cytokines are found in inflammatory foci.^7,8 Biological activities are mediated by cytokines either directly on immune cells or upon the adhesion molecules with which immune cells interact and may therefore be considered pro-inflammatory. Interleukin-1 (IL-1) and tumor necrosis factor (TNF), have been known to play a major role in coordinating

mechanisms which command

inflammation, the production is increased by other cytokines like IFN gamma, IL-3, GM-CSF. GM-CSF produces other cytokines, like IL-8 and the macrophage chemo-attractant protein 1 (MCP-1), the chemotactic properties of which participate in the recruitment of leucocytes within the focus of inflammation. TGF–β possesses a number of anti-inflammatory activities and, like IL-4 and IL-10, which can inhibit IL-1 and TNF production.⁸ Several matrix metalloproteinases have been detected in crevicular fluids and tissues of inflamed human gingiva as they have the pro- inflammatory cytokines (IL-1 and TNF-α) which regulate their transcription.⁹ It has been well established that a cytokine network is activated in the periapex in response to bacterial infection, and that a Th1-modulated pro-inflammatory pathway may predominate during periapical bone destruction.¹⁰ IL-1,TNF and IL—6 have been primarily recognized in cartilage inflammatory sites and the IL-10 family cytokines are now recognized as essential for maintaining the integrity and homeostasis of tissue epithelial layers.^11,12

Cytokines in gingival and periodontal diseases

The cytokines and nitric oxide released in periodontal lesions have been reported to play a protective role in bacterial infection and to relate to the process of inflammation, the expression of IL-6 was shown to reflect inflammation in gingival tissue, and iNOS has been suggested to be involved in the inflammatory process in periodontitis.¹³

IL-1β is likely to be an important mediator in the pathogenesis of periodontal disease.¹⁴ Lymphotoxin (LT) and IL-1

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catabolic activities, and play key roles in periodontal tissue breakdown. They induce fibroblasts and macrophages to produce neutral metalloproteinases such as procollagenase and prostromelysin, the serine proteinase urokinase-type plasminogen activator (μ-PA), tissue inhibitor of metalloproteinase (TIMP), and prostaglandins, and these enzymes degrade the extracellular matrix components.¹⁵ IL4 and IFNγ levels in the patients with chronic periodontitis compared to those of healthy gingival samples have shown a significant reduction. It appeared that in the periodontitis pathogenesis, as well as TH1 and TH2 responses, IL17 causes the host immunological response to the periodontal pathogenesis.¹⁶

Ratios of gingival cytokines i.e. interleukin (IL) IL-1beta, IL-6 and IL-8 has been observed to change with increased sulcular depth, this fact has been proposed to be used as an adjunct to monitor the periodontal diseases.¹⁷

Cytokines in Oral Lichen Planus

Oral Lichen Planus (OLP) there is a chronic and cell-mediated, immune damage to the basal keratinocytes in the oral mucosa that are recognized as being antigenically foreign or altered with the identity of the target antigen remaining unknown. It is likely that cytokines released by the affected keratinocytes, and the associated inflammatory infiltrate, play a key role in the selective recruitment of the T-cell-dominated infiltrate that characterizes OLP. A delicately fabricated unifying hypothesis was presented by Sugermann PB at al18 in 2006, examining the role of TNF-α in initiation and progression of oral lichen planus.

Previous studies have reported an increase in the levels of IL-1β, IL-4, IL-6, IL-10, IL-18 granulocyte colony-stimulating factor, tumor necrosis factor, CD4+, CD8+, Langerhans cells, ICAM-1 and VCAM-1, and low levels of IFN-γ in patients of OLP compared to normal or inflamed gingival tissues.19,20,21,22 Simark- Mattsson C et al²³ have shown that both pro- and anti-inflammatory cytokines, i.e., mixed T-helper 1 (TH1) and TH2 cytokine profiles, are generated simultaneously by a limited number of cells in chronic lesions of OLP. NF-κB-dependent inflammatory cytokines may be detected at increased levels in certain oral fluids, which may have diagnostic and prognostic potential for monitoring disease activity and making therapeutic decisions in patients with OLP.²⁴

Cytokines in Oral Submucous Fibrosis Oral submucous fibrosis (OSF) is a chronic debilitating disease and a premalignant condition of the oral cavity.

Cytokines and growth factors produced by inflammatory cells within the lesion may promote fibrosis by inducing proliferation of fibroblasts, upregulating collagen synthesis and down-regulating collagenase production. Activation of transforming growth factor-β signaling has been postulated as the main causative event for increased collagen production in OSF.^25-33 Previous studies have shown an upregulated expression of interleukin α (IL-1α) and β, IL-6 interferon (IFN) β, transforming growth factor β (TGF-β), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF);

downregulation of IFN- γ.25 It has been suggested that the effect of IFN-γ on collagen synthesis appears to be a key to

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lesional injections of the cytokine may have a significant therapeutic effect on OSF.²⁷

Cytokines in Bone Pathophysiology Both osteoblasts and osteoclasts are derived from progenitors that reside in the bone marrow; osteoblasts belong to the mesenchymal lineage of the marrow stroma, and osteoclasts to the hematopoietic lineage. The development of osteoclasts from their progenitors is dependent on stromal-osteoblastic cells, which are a major source of cytokines that are critical in osteoclastogenesis, such as interleukin-6 and interleukin-11. It has been established during the past few years that interleukin(s)-1, -6, -11 (IL-1, IL-6, IL-11), and tumor necrosis factor (TNF) can stimulate osteoclast development and thereby the process of bone resorption.

Moreover, upregulation of the production and/or action of IL-6 has been implicated in the pathogenesis of disease states characterized by excessive osteoclastic bone resorption, including the osteopenias associated with loss of either ovarian or testicular function.⁴

Tsuda E et al³⁴ isolated a novel cytokine from the human fibroblasts that specifically inhibit osteoclastogenesis; the osteoclastogenesis Inhibitory Factor (OCIF). Previous studies have demonstrated the role of sex steroids with bone pathophysiology, the protective effects of estrogens and androgens on the skeleton are mediated through their ability to inhibit IL-6 production.³⁵

Cytokines in Orthodontics

Migrated immune cells along with native cells such as fibroblasts and osteoblasts

produce inflammatory cytokines that include lymphocyte- and monocyte- derived factors, colony-stimulating factors, growth factors, and chemotactic factors. It has been suggested that cytokines and other inflammatory markers, such as prostaglandin E2, may activate bone remodeling characterized by bone resorption in the compression region and bone deposition in the tension region of the periodontal ligament (PDL). High concentrations of inflammatory cytokines such as interleukin-1 (IL-1), IL-2, IL-3, IL-6, IL-8, tumor necrosis factor-α (TNFα), interferon-γ (IFNγ), and osteoclast differentiation factor have been found in the gingival crevicular fluid surrounding moving teeth. Associations exist between prostaglandin E2 (PGE2) and interleukin-1β (IL-1β) and pain, velocity of tooth movement, and treatment mechanics. Interleukin-1β and PGE2 show different patterns of up-regulation, with IL-1β being more responsive to mechanical stress and PGE2 more responsive to synergistic regulation of IL- 1β and mechanical force. Thus, at the cellular level, the use of light continuous forces for orthodontic treatment is recommended.^36-40

Previous research has shown an almost two-fold increase in the levels of TNF-α, IL-1β, IL-6, IL-8 (pro-inflammatory cytokines) isolated from the gingival sulcus during stages of tooth movement in patients undergoing orthodontic treatment.

It was suggested that the orthodontic forces activate the microenvironment surrounding the periodontal tissue resulting in a surge of cellular events elicited by these proinflammatory cytokines.^37,38

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An understanding of these biomessenger molecules and their biology is overwhelming and intimidating, it has its roots firmly adherent to the pathophysiologic processes and their possible treatment protocols.

The unambiguous explanation of disease pathogenesis can be uncovered by an understanding the association of cytokines.

This may also guide in appreciation of the molecular and therapeutic aspects and diagnostic medicine. Hence the correct and auxillary insight into the cytokine physiology is an imperitive stride in optimizing their beneficial use and advancing our acquaintance of the biogenesis of disorders. By the help of cytokines it is likely that we will be able to control the harmful effect of inflammation and of tissue-damaging immune reactions.

Moreover commercially available recombinant cytokines can be administered to treat or to enhance immunity against cancer or microbiological infection. A few cytokines are commercially available and some are under evaluation; there is a likelihood that the beneficial effects of the cytokines translated in terms of better clinical outcomes, reduction in number of blood product transfusion, lesser antibiotic requirements, shorter period of hospitalization and easy chemotherapy dose escalation may outweigh the price burden of these products.

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How to cite this article: Sethi S, Aggarwal P. Cytokines and Oral Pathology – An Intricate Liason. Arch of Dent and Med Res 2015;1(2):24-32.