# The Interaction of Cytokines in Orthodontics: A Systematic Review
## 1 Introduction  
Cytokines (cyto-, cell and -kinos, movement), also called \"molecular words\", are low-molecular-weight proteins. Via specific membrane receptors, they function to induce and/or stimulate reactions in the same cell that produces them (autocrine activity), in neighboring cells (paracrine activity) or at a distance, and through the bloodstream (endocrine activity) (Figure 1) [1, 2]. They are also referred to as \"immunomodulatory agents\", since they play a very important role in both innate (by activating macrophages and natural killer cells) and acquired immune responses, both humoral and cellular (by activating T-lymphocytes and B-lymphocytes). They are produced and released by cells as soon as the immune system detects the presence of a pathogen and other stimuli, such as the orthodontic force [3, 4, 5]. Cytokines can have the following properties: redundant (amplified effect by action of multiple cytokines on the same cell); pleiotropic (action on multiple cell types); synergistic (associated with other cytokines); or antagonistic (on the impact of another cytokine) [6; 7]. To date, 36 cytokines have been isolated in humans. There is no definitive classification because different cell types can produce the same cytokine, and a single cytokine can have multiple functions [8]. However, they could be classified according to the producing cells, lymphokines (from lymphocytes) or monokines (from monocytes), or according to their activities:  
1. Proinflammatory cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8(IL-8) and tumor necrosis factor (TNF), deputed to control inflammation, fever, sleep rhythm, hematopoiesis and reabsorption [9; 10];
2. Immunoregulatory cytokines: IL2, IL3, IL4, IL5, IL7, IL10, IL12. These ILs, in fact, control the immune system response by stimulating differentiation into natural killer cells and B lymphocytes for antibody production [11];
3. Effector cytokines: interferons, chemokines, and stimulating factors (CSFs) that modulate defense processes toward infectious agents and neoplastic processes [9]. Studies show how the occurrence of various disease states (organ failure, fibrosis, and chronic inflammation) are related to insufficient cytokine production or secretion [6; 12]. An interesting correlation was found between OT and the presence of cytokines [13; 14]. OT, whatever the method, aims to achieve a stable, functional and balanced occlusion. This requires the need to make modifications of both the bony bases and the dental elements. The forces applied for orthodontic movement generate areas of tension and compression at the level of the PDL, resulting in remodeling of the entire periodonotin (PDL, alveolar bone and gums). The PDL immediately undergoes blood flow changes through the release of cytokines, growth factors, and bacterial flora growth factors, following signals emitted by other molecules such as eicosanoids, substance P and calcitonin gene-related peptide, and cyclic adenosine monophosphate (cAMP) [15; 16; 17]. Cytokine production and migration affects bone and soft tissue metabolism by acting on NF kappa B ligand receptors (RANKL), osteoprotegerin (OPG), matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) [18; 19]. Study findings revealed elevated concentrations of proinflammatory cytokines and markers of tissue and bone metabolism in gingival crevicular fluid (GCF) following the application of orthodontic forces [20; 21]. Increased levels were observed after 4 h and persisted for up to 6 weeks. At the site of compression, an increase in IL-1 beta and  
Figure 1: Cytokines act primarily in local form, affecting both the producing cell itself (autocrine activity) and adjacent cells (paracrine activity), rather than exerting significant effects on cells and tissues distant from the site of production (endocrine activity). IL-8 was recorded after 4 h, MMP-9 after 7 and 42 days, and RANKL after 42 days [18; 22].