**7.4.** *IL-1β, IL-6,* **and** *TNF-α* **and other inflammatory mediators in periodontium**

The effects of cytokine in the response of the tissue to orthodontic forces are connected to the creation of nitrogen oxide (NO), which is known to be one of the important regulators of bone remodeling. For the creation of NO, the activity of two enzymes is necessary: inducible nitrogen-oxide synthesis (iNOS) and endothelial nitrogen-oxide synthesis (eNOS). The gene expression of these two enzymes is activated by pro-inflammatory (*IL-1β*, *TNF-α*) and anti-inflammatory (*IL-4, IL-10, TGF*-*β*) cytokines, which are created during the resorption and reparation of bones [36]. At the experimental model (rat), it was noticed that after the application of the orthodontic force iONS is the mediator in the bone resorption caused by the inflammation at the compression zone and eNOS in the bone creation at the tension zone [37]. Orthodontic forces express their effect to the dental pulp initiating the responses of fibroblast in it. Even though it is considered that the reactions of the pulp to the orthodontic treatment are very small, they still bring about changes in the blood flow and releasing of *IL-1β, IL-6,* and *TNF-α* from the pulp fibroblast, which results in its inflammation [17]. The process is specifically related to the pulp innervations and neurogenic mechanisms [38], and in the case of more expressed effect of mechanical forces may lead to the resorption of the tooth root [39].

The orthodontic tooth movement is accompanied by releasing neuropeptides from peripheral endings of sensor nerves, which permeate the dental pulp and periodontium, as well as from the inflammatory cells localized in the periodontal tissue. Released neuropeptides regulate the microcirculation of the pulp and mediate in inflammatory processes during remodeling of bones, characteristic for orthodontic tooth movement [19]. Such neural effect, which is generally called "neurogenic inflammation," is connected to the pain, which partially occurs during stretching and pressing of the tissue under the influence of mechanical forces and partially because of the

The main mediators of neutrogenic inflammation are neuropeptides, SP and CGRP, which are proven to have vasodilatation effect, increase vascular permeability and participate in the inflammatory processes related to the damage, and recovery of the tissue [41]. The increase of the level of these neuropeptides is recorded in gingival fluid immediately after the effect of orthodontic forces, which occurs simultaneously with the increase of the level of pro-inflammatory cytokines *IL-1β*, *IL-6*, *TNF-α* in this liquid [42]. Although the ratio of neuropeptides and cytokines included in the process of inflammation, which occurs during the orthodontic tooth movement, is still not entirely clear, the data show that SP and CGRP stimulate the excretion of *IL-1β*, *IL-6*, and *TNF-α* from fibroblast of human dental pulp, but they do not work synergistically [16, 42]. The neuropeptide SP is included in the resorption phase of the reshaping of the bone during the orthodontic tooth movement by stimulating the creation of RANKL in the cells of human dental pulp similar to fibroblasts [43]. The SP expression may be prevented by *TGF*-*β* [44], whose excretion overlaps with the initial stage of reparation of

The effects of neuropeptides to cytokines are not unidirectional [19, 38]. *IL-1β* and *TNF-α* secreted from inflammatory cells after the stimulation with SP lead to the creation of nerve

interaction of numerous inflammatory mediators with local pain receptors [38, 40].

**7.3.** *IL-1β, IL-6,* **and** *TNF-α* **and "neurogenic inflammation"**

periodontal tissue.

42 Current Approaches in Orthodontics

Apart from mutual interactive effects in the processes of inflammatory responses and bone remodeling during the orthodontic tooth movement, *IL-1β, IL-6*, and *TNF-α* frequently have effects in the combination with various other bioactive structures included in these processes.

After the primary inflow to the inflammation location and the initiation of an early stage of periodontal remodeling, these cytokines start the second tide of cytokine regulation of this process by "introducing" other relevant cytokines. It is shown that an early but not initial phase of the orthodontic tooth movement is followed by the increase of the level of *IL-8* in gingival fluid [6, 45], which is known to regulate inflammatory responses in periodontium in combination with other cytokines [46]. *IL-1β, IL-6,* and *TNF-α* stimulate the creation of *IL-8* in monocytes, macrophages, epithelial cells, and fibroblasts of periodontium, so that the IL-8 mechanism of feedback could initiate the creation of *IL-1β, IL-6*, and *TNF-α* [6], when periodontal system moves from resorptive to formative stage of bone remodeling. With IL-8 during the orthodontic treatment, the level of IL-2 also increases and it is considered to be the indicator of inflammatory activities in periodontium [47].

The increased expression of pro-inflammatory cytokines in human periodontium, due to orthodontic forces, is followed by prominent increase in the level of prostaglandin E<sup>2</sup> (*PGE2 )*. This prostaglandin, which is created in various cells of mammals as one of the intermediary products of metabolism and arachidonic acid, is the mediator in the sustaining of local homeostasis, modulating numerous physiological processes including the inflammation. During the resorptive phase of bone remodeling caused by mechanical stress and initiated by acute inflammatory response, *PGE2* is created in cells of periodontal ligament (mechanically deformed osteoblasts and gingival fibroblasts), stimulating the creation of osteoclasts, which intensifies the bone resorption [16]. In this process, *IL-1β* and *TNF-α* express synergistic effects to the creation of *PGE2* stimulating the fibroblasts to the synthesis of this prostaglandin. The increased level of *PGE2* in the reaction results in the decrease of the expression of proinflammatory cytokines [48] and, consequently, the inhibition of the inflammatory response and stimulation of the bone formation. This dual role of *PGE2* (resorption on the one hand and bone formation on the other) is interpreted by the possibility of prostaglandin directing in different manners the bone cells: for resorption those in bone marrow and for the bone formation those at their surface.

The inflammatory response, which occurs during the orthodontic tooth movement, is followed by the increase of β<sup>2</sup> expression, microglobulin (β<sup>2</sup> -*MG*), glycoproteins, which together with the pro-inflammatory cytokines initiate the process of bone remodeling [18]. β<sup>2</sup> -*MG* occurs in soluble form in different bodily fluids of organisms including the gingival fluid and also is in the composition of the main histocompatible locus of I class (MHC class I), which is expressed at the surface of various cells, mostly lymphocytes and monocytes. In the process of bone remodeling, after a mechanical stress, β<sup>2</sup> -*MG* is included as a regulatory factor of the bone metabolism, with the function of a stimulator of the osteoclast activity in the resorption stage and the function of the increase of the binding for bone cells *IGF-I* in the stage of bone formation [49].

**8. Conclusion**

**Author details**

\*, Jasna Pavlovic<sup>2</sup>

Address all correspondence to: amilavujacic@gmail.com

3 School of Agriculture and Food Science, Dublin, Ireland

Journal of Dental Research. 2008;**87**:414-434

pean Journal of Oral Sciences. 2008;**116**:89-97

Amila Vujacic<sup>1</sup>

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**Note**

The early stage of the tooth movement is followed by the inflammatory response of the tissue to the effects of the mechanical force, which are conducted and regulated by pro-inflamma-

The Role of Cytokines in Orthodontic Tooth Movement http://dx.doi.org/10.5772/intechopen.80078 45

The execution of this chapter was financially supported by the Ministry for Science and

and Aleksandra Konic-Ristic<sup>3</sup>

[1] Sandstedt C. Einige Bettrage zur Theorie der Zahnregulierung. Nordisk Tandlӓkare

[2] Davidovitch Z, Nicolay O, Ngan PW, Shanfeld JL. Neurotransmitters, cytokines and control of alveolar bone remodeling in orthodontics. Dental Clinics of North America.

[3] Callard R, George AJT, Stark J. Cytokines, chaos, and complexity. Immunity. 1999;**11**:

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tory cytokines *IL-1β, IL-6*, and *TNF-α*, acting as mutual activators and inhibitors.

Technological Development of the Republic of Serbia (project no. OI175061).

1 The Faculty of Medicine, The University of Pristina, Kosovska Mitrovica, Serbia

2 School of Medicine, University of Pristina, Kosovska Mitrovica, Serbia

Apart from pro-inflammatory cytokines and other pro-inflammatory substances, during the orthodontic tooth movement to gingival fluid, various metabolites are released, too. For lactate-dehydrogenase (*LDH*) [21] and metalloproteinase 8 [20], it is shown that they increase their level or the activity simultaneously with pro-inflammatory cytokines, in approximately the same time, so it is considered that their existence reflects the increased periodontal remodeling caused by orthodontic forces primarily at early stages of this process. *LDH* is intracellular, cytoplasmic enzyme, which is released outside the cell under conditions of cellular necrosis or tissue degradation. It is believed that the increase of the *LDH* level at gingival fluid during the orthodontic tooth movement follows the process of bone resorption [21]; metalloproteinase 8 is the isoform of the enzyme of collagenase, which is released from periodontal fibroblasts due to the effects of mechanical forces. In the increased level in gingival fluid, it emerges during the initial stage of the orthodontic tooth movement, expressing the increased periodontal remodeling caused by these forces [20].

The damage of dental tissues caused by inflammation and its reparation are based on many elements and their coordination inside and outside cells. Even though there are differences between pathological inflammatory changes and those which accompany mechanically caused reshaping of tissues, the basic cellular responses to stimuli, regardless of their nature, express essentially the same properties [50]. Our researches of changes of individual integral parts of the immune system and ECM in normal and inflammatory gingiva [51–53] were the basis for the examination of the expression of IL*-1β, IL-6*, and *TNF-α* and their mutual relation in gingival fluid and tissue of gingiva of children and adults who underwent the orthodontic treatment. Analyzing the causes of gingival fluid and tissue of free gingiva of orthodontically treated teeth (experimental teeth) and their nontreated antagonists (control teeth) in four different moments in time ("zero" hour, 24th hour, 72nd hour, and 168th hour after the application of the separator), we have reached the knowledge about the dynamics of the change in the local cytokine network during the initial stage of orthodontic tooth movement and differences existing in the amplitude of these changes between children and adult examinees [54]. The results led us to assume that in the first moments of orthodontic treatment, the constitutive creation of pro-inflammatory cytokines is created and then it is overcome in the following time intervals by more expressive reaction of cells to the effects of mechanical force. The time coincidence of quantitative changes of *IL-1β, IL-6*, and *TNF-α* in gingival fluid and tissue expression of orthodontically treated teeth indicate that these three cytokines could be in specific interdependence during the early stage of the orthodontic tooth movement. Put into the context of the concept about the pharmacological modulation of the tooth movement, especially the aspect which leads the acceleration of the process of tooth movement in the connection with the local application of cytokine, the results could be very useful.
