Abstract

The term periodontal disease encompasses a wide variety of chronic inflammatory conditions of the periodontium, including gingivitis and periodontitis. The gingival disease is an infectious process, which occurs due to the progression of untreated gingivitis. It is characterized by a destructive inflammatory process that affects the supporting tissues of the teeth, which causes the loss of the dental organs. As a result of inflammation, a wide range of cytokines and inflammatory mediators together contribute to tissue degradation and bone resorption. However, some molecules that have not been studied in the inflammatory process of this disease, such as the macrophage migration inhibitory factor (MIF) which is considered an important cytokine of the innate immune system; it is expressed constitutively in immune and nonimmune cells, and it is released immediately against bacterial stimuli, hypoxia, and proliferative signals. MIF has been described in some chronic degenerative, inflammatory, and autoimmune diseases. Previous studies have described that in murine models of periodontitis, MIF promotes the activation and differentiation of osteoclasts that could position this cytokine in the immunopathogenesis of gingival disease in humans.

Keywords: macrophage migration inhibitory factor, cytokine, gingival disease, periodontitis, osteoclastogenesis

### 1. Introduction

The periodontium is considered an organ constituted by a group of hard tissues (alveolar bone and cement) and soft tissues (periodontal ligament and gingiva). These tissues support the dental organs for a proper function in the oral cavity [1].

The gingiva is a specific oral, physical barrier (Figure 1) [2], which is a dynamic environment and continuously stimulated by the microbial imbalance, where

The subsequent signal translation activates signaling pathways that promote the

Immune Response in Gingival Disease: Role of Macrophage Migration Inhibitory Factor

Chemokine, cytokines, and inflammatory mediators such as leukotrienes increase vascular permeability and the expression of adhesion molecules that stimulate the infiltration of non-resident cells to the tissues such as neutrophils, macrophages, and lymphocytes [6]. Therefore, an inflammatory environment is initiated locally that includes prostaglandins, matrix metalloproteases, complement proteins,

Inflammation is continued by macrophages that increase the concentration of

The pro-inflammatory microenvironment could compromise the integrity of the alveolar bone that supports the dental organs which are maintained by the balance between the reabsorption of the old bone by the osteoclasts and the formation of the new bone by the osteoblasts; however, in periodontitis (PE), the cycle of bone remodeling is altered in favor of the resorption [14]. Key effectors in the microenvironment of bone resorption involve the molecule triad, receptor activator of nuclear factor-kappa B ligand (RANKL), receptor activator of nuclear factor-kappa B (RANK), and decoy receptor osteoprotegerin (OPG) [15, 16]. RANKL, which is produced by osteoblasts, stromal cells, T cells, and other sources, activates RANK on the surface of osteoclasts and osteoclast precursors [16]. The process of

Bone resorption. The osteoclast activity is regulated by the expression and interaction of RANK-RANKL-OPG

tumor necrosis factor alpha (TNF-α) and interleukin 1, 6 (IL-1, IL-6); at this moment more neutrophils are recruited in the furrow to try to control the infection [3, 11]. If the bacterial infection is not resolved by the inflammation, the antigens are captured, processed, and shown by antigen-presenting cells that activate naïve CD4 T lymphocytes at the subtype Th17 [13]. The profile of Th17 lymphocytes present in the gingival sulcus secretes cytokines such as IL-17 and IL-22 that

expression of pro-inflammatory cytokines and chemokines [11].

DOI: http://dx.doi.org/10.5772/intechopen.82026

enhance inflammation to eliminate extracellular bacteria [11].

and cytokines [12].

Figure 2.

47

[17]. Periodontal disease increased the resorption bone.

#### Figure 1.

Gingiva. The epithelial junction is a specific oral physical barrier.

homeostasis is frequently altered, which leads to that entails to an inflammatory event at the site [3].

Inflammatory cytokines and immune and nonimmune cells play, in the periodontium, an important defensive role in the gingival barrier [4]. However, the intimate relation between the epithelial junctions and the surface of the tooth can be interrupted by routine actions such as chewing and brushing and the formation of the biofilm, which can cause bacterial translocation [5].

## 2. Gingiva disease

The interaction between the gingival epithelial cells and the main pathogens (Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Tannerella forsythia) [6] (Figure 1) is one of the first events that start with immunological response at the site, orchestrated by pro-inflammatory mediators as cytokines that can lead to gingival disease [3].

The gingival disease is defined as an inflammatory disorder initiated on the surface of the soft tissues, where the persistent inflammation can promote the destruction of the periodontium [7].

The disease occurs by a complex interaction between the microbial environment and the immune response of the host, which results in altered bone metabolism and connective tissue destruction [8]. It has been proposed that periodontopathogens are necessary but insufficient to promote the destruction of tissues and develop periodontal lesions because most of the damage is caused by the subversion of the host immune response [6].

#### 2.1 Immune response in the gingiva

The adhesion and colonization by periodontopathogens in the gingiva trigger inflammatory through the liberation of endotoxins and bacterial products from the bacteria [9] which are recognized by the pattern recognition receptor (Toll-like receptors, cytoplasmic nucleotide oligomerization domain-like, lipopolysaccharidebinding protein, CD14) expressed in resident cells of the gingiva such as epithelial cells, fibroblasts, macrophages, neutrophils, and dendritic cells [10].

#### Immune Response in Gingival Disease: Role of Macrophage Migration Inhibitory Factor DOI: http://dx.doi.org/10.5772/intechopen.82026

The subsequent signal translation activates signaling pathways that promote the expression of pro-inflammatory cytokines and chemokines [11].

Chemokine, cytokines, and inflammatory mediators such as leukotrienes increase vascular permeability and the expression of adhesion molecules that stimulate the infiltration of non-resident cells to the tissues such as neutrophils, macrophages, and lymphocytes [6]. Therefore, an inflammatory environment is initiated locally that includes prostaglandins, matrix metalloproteases, complement proteins, and cytokines [12].

Inflammation is continued by macrophages that increase the concentration of tumor necrosis factor alpha (TNF-α) and interleukin 1, 6 (IL-1, IL-6); at this moment more neutrophils are recruited in the furrow to try to control the infection [3, 11]. If the bacterial infection is not resolved by the inflammation, the antigens are captured, processed, and shown by antigen-presenting cells that activate naïve CD4 T lymphocytes at the subtype Th17 [13]. The profile of Th17 lymphocytes present in the gingival sulcus secretes cytokines such as IL-17 and IL-22 that enhance inflammation to eliminate extracellular bacteria [11].

The pro-inflammatory microenvironment could compromise the integrity of the alveolar bone that supports the dental organs which are maintained by the balance between the reabsorption of the old bone by the osteoclasts and the formation of the new bone by the osteoblasts; however, in periodontitis (PE), the cycle of bone remodeling is altered in favor of the resorption [14]. Key effectors in the microenvironment of bone resorption involve the molecule triad, receptor activator of nuclear factor-kappa B ligand (RANKL), receptor activator of nuclear factor-kappa B (RANK), and decoy receptor osteoprotegerin (OPG) [15, 16]. RANKL, which is produced by osteoblasts, stromal cells, T cells, and other sources, activates RANK on the surface of osteoclasts and osteoclast precursors [16]. The process of

#### Figure 2.

Bone resorption. The osteoclast activity is regulated by the expression and interaction of RANK-RANKL-OPG [17]. Periodontal disease increased the resorption bone.

homeostasis is frequently altered, which leads to that entails to an inflammatory

Inflammatory cytokines and immune and nonimmune cells play, in the periodontium, an important defensive role in the gingival barrier [4]. However, the intimate relation between the epithelial junctions and the surface of the tooth can be interrupted by routine actions such as chewing and brushing and the formation of the biofilm, which can cause bacterial translocation [5].

The interaction between the gingival epithelial cells and the main pathogens (Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Tannerella forsythia) [6] (Figure 1) is one of the first events that start with immunological response at the site, orchestrated by pro-inflammatory mediators as cytokines that

The gingival disease is defined as an inflammatory disorder initiated on the surface of the soft tissues, where the persistent inflammation can promote the

The disease occurs by a complex interaction between the microbial environment and the immune response of the host, which results in altered bone metabolism and connective tissue destruction [8]. It has been proposed that periodontopathogens are necessary but insufficient to promote the destruction of tissues and develop periodontal lesions because most of the damage is caused by the subversion of the

The adhesion and colonization by periodontopathogens in the gingiva trigger inflammatory through the liberation of endotoxins and bacterial products from the bacteria [9] which are recognized by the pattern recognition receptor (Toll-like receptors, cytoplasmic nucleotide oligomerization domain-like, lipopolysaccharidebinding protein, CD14) expressed in resident cells of the gingiva such as epithelial

cells, fibroblasts, macrophages, neutrophils, and dendritic cells [10].

event at the site [3].

Gingiva. The epithelial junction is a specific oral physical barrier.

Gingival Disease - A Professional Approach for Treatment and Prevention

Figure 1.

2. Gingiva disease

can lead to gingival disease [3].

host immune response [6].

46

destruction of the periodontium [7].

2.1 Immune response in the gingiva

osteoclastogenesis begins by the binding of RANK-RANKL and can be interrupted by OPG that functions as a decoy receptor that blocks the binding of RANKL to RANK (Figure 2) [17].

stimulates the release of other cytokines, such as TNF-α, IFN-γ, IL-1β, IL-6, IL-8,

MIF also participate in the modulation of the expression of other proinflammatory molecules, including the same MIF, nitric oxide and cyclooxygenase 2 (COX-2), and prostaglandin 2 (PGE2), perpetuating the inflammatory environ-

Immune Response in Gingival Disease: Role of Macrophage Migration Inhibitory Factor

MIF plays a critical role in the regulation of the innate immune response, through the modulation of TLR4. Activation of TLR4 results in the production of pro-inflammatory mediators, including MIF, which induces the recruitment of

Although MIF was identified for the first time as an inhibitor of macrophage migration, subsequent studies revealed that in the presence of inflammatory mediators, it is also capable of leukocyte extravasation [24]. This cytokine can have a similar function to chemokines while it is in interaction with the

chemokine receptors CXCR4 and CXCR2 to promote the recruitment of inflamma-

In this way, MIF participates in the adhesion of monocytes to the vessel wall and its transendothelial migration [25]. This immobilization of cells to the endothelial surface is mediated by the action of chemokines that prevent these cells from continuing their circulation, promoting the immobilization and transmigration of

The pro-inflammatory, chemoattractant, and osteoclastogenic characteristics of MIF make it a cytokine with an important role both in the initiation and progression

As mentioned above, MIF is a cytokine produced by immune and nonimmune cells; therefore the source of MIF in periodontal tissues can be diverse including

The studies related to MIF and periodontal disease are few; however, the existing ones have given the guidelines to introduce this cytokine to its patho-

ment, by positive feedback to the inflammatory response [22, 23].

inflammatory cells, including neutrophils [19].

and IL-12 in inflammation [19].

DOI: http://dx.doi.org/10.5772/intechopen.82026

3.2 MIF chemotactic activity

the cells through the endothelium [26].

3.3 MIF and periodontal disease

of periodontal disease (Figure 4).

3.3.1 MIF expression in gingival tissue

inflammatory cells as cells resident in tissues [19].

tory cells [19].

physiology.

Figure 4.

49

MIF in periodontal disease.

The pro-inflammatory cytokines are proteins that have a principal role in the control, direction, amplitude, and duration of the immune response. They allow contact within the immune system and communication with other organs and tissue systems [8]. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine; MIF is an important mediator of the innate immune response [18]; however, there are a few studies that describe its participation in PE, for its characteristics it can lead the environment of the inflammatory response in the disease.
