# The Interaction of Cytokines in Orthodontics: A Systematic Review
## 1 Introduction
Vasodilation and leukocyte invasion, signs of the onset of the inflammatory state, occur due to the action of proinflammatory cytokines, such as IL-1 beta, IL-2, IL-5, IL-6, IL-8, TNFalpha, interferon-gamma and Granulocyte-Macrophage Colony-Stimulating Factor) GM-CSF. In contrast, anti-inflammatory cytokines such as IL-4 and IL-10 intervene in the healing process [23; 24; 25; 26; 27]. IL-1 beta, produced predominantly by activated monocytes, induces osteocl activity as a consequence of the acute phase [28]. Notable elevations in IL-1 beta, IL-8, TNFalpha, MMP-9, and TIMP 1 and 2 were found at the tension sites adjacent to the dental elements in all time spaces following force application [18; 19]. IL-1, TNF-alpha, and IL-6 increase bone resorption by modulating the binding of RANKL, stimulating osteoclast maturation, also caused by a reduction in the osteoblastic production of OPG, receptor of RANKL, inhibiting its differentiation [29; 30]. Orthodontic movement also results in soft-tissue remodeling, which has been studied on the concentrations of metabolites released in GCF. Enzymes such as MMPs and tissue inhibitors of matrix MMPs (TIMPs) metabolize soft tissue [31; 32]. Collagen fibers are degraded by collagenases, specifically MMP-1 and MMP-8, while denatured collagen is degraded by gelatinases, such as MMP-2 and MMP-9. In the GCF at compression and tension sites, an increase in the concentration of MMP-1, MMP-8, MMP-2, MMP-9, and TIMP-1 was found, varying in amounts according to the interval of force application (e.g.,MMP-1 shows very high levels already after the first hour of force application, while MMP-2 reaches higher basal levels after 8 h) [33; 34]. Alterations in the orthodontic patient's physiometabolic status also modifies the periodontal complex's inflammatory response during treatment. Chronic pathological conditions, such as type 2 diabetes mellitus (DMT2), manifested increased concentrations of advanced glycation metabolite levels and GCF proinflammatory chemokines [35; 36; 37; 38; 39; 40; 41]. In obese adolescent patients, there is already a pre-existing situation of periodontal tissue inflammation, recorded by increased levels of adipocytes, leptin, and ressition in GCF [42; 43]. With regard to chronic diseases, research shows that a cytokine response can also occur in temporary, acute-phase diseases, such as in SARS-CoV-2 infection [44; 45]. The correlation between COVID-19 patients and cytokine release is a topic of great interest in scientific research, as it is recognized that COVID-19 elicits an inflammatory immune response involving various types of cytokines [46; 47]. In this situation, numerous pro-inflammatory cytokines, including TNF, interferon-\(\gamma\), IL-1, IL-6, IL-18, and IL-33, are released uncontrollably, giving rise to a cytokine storm. The entire pathological process, triggered by defects in the cytolytic activity of lymphocytes, continues with increased macrophage activity and hyperactivation of the immune system, culminating in cytokine storm. In patients who contracted COVID-19 during OT, increased cytokines were found in periodontal tissues [48; 49; 50; 51]. The increased cytokine response occurs in the more acute stages, and the control of the periodontal situation could be more difficult and, during OT, could affect the final outcome. The acute phase, in this type of infection, is also quite long, encompassing the entire convalescence period. In some patients, this immune response may become excessive, leading to an overproduction of cytokines and resulting in a state of systemic inflammation. In these patients, greater orofacial pain, after 24 h of OT, was also related to higher levels of the proinflammatory cytokine IL-1\(\beta\) before and during tooth movement, and a higher concentration of TNF-\(\alpha\) was found compared with non-obese adolescents. No difference was found in the speed of tooth movement during the initial week of orthodontic therapy between obese and non-obese patients [52; 53].