# The Interaction of Cytokines in Orthodontics: A Systematic Review
## 1 Introduction
Studies on failures in the stability of mini implants, increasingly used as skeletal anchors in OT in both adults and adolescents, have evaluated genetic, biomolecular and inflammatory aspects [54; 55]. The single-nucleotide polymorphism (SNP) of IL-1(IL-1\(\alpha\) and IL-1\(\beta\)) and IL-6 can recognize the same receptor on the same target cell, resulting in the same biological responses and amplifying them. Tissue trauma, derived from the same mini-implant insertion, the presence of plaque around peri-implant tissues and crevicular fluid, the application of forces, and smoking determine the release of pro-inflammatory cytokines (IL-1\(\beta\), IL-2, IL-6, and IL-8) around the device [56; 57]. This results in an activation of lymphocytes,macrophages, endothelial cells, neutrophils, and prostaglandins with the appearance of fibrinolytic and osteocl activity and mobilization and failure of the miniscrew [58; 59]. Higher concentrations of IL-1\(\beta\), IL-6, and IL-8 were recorded after at 8 h implantation, remaining elevated during the first 24 h. This is likely related to tissue trauma following implant placement and the immediate application of forces. These findings imply that by controlling orthodontic pressure, cytokine concentrations and implant detachment could be reduced [56; 60; 61]. Studies have been carried out on the different inflammatory response between self-ligating brackets and conventional brackets. Data report a more amplified response and a higher concentration of cytokines and bacteria in self-ligating brackets [61; 62]. Therefore, in patients at risk of periodontal disease and root resorption, the design of the attachment has great relevance. While evaluating the biocompatibility and possible toxicity of resin surface sealants, there were no different concentrations between IL-6 and IL-8 levels among the different resins used [63; 64]. Instead, a diversity of individual anti-inflammatory response was found. Therefore, OT today must involve careful evaluation of each individual patient to tailor the treatment accordingly. This approach is fundamental to improving clinical outcome and preserving patients' periodontal health [65; 66]. The overlapping cellular response to OT in premenopausal and postmenopausal women, given that, at the start, the latter have increased bone turn markers in GCF, more specifically in RANKL and osteopontin (OPN) levels, indicates the safety of OT in postmenopausal women as well [67; 68]. In male patients undergoing fixed OT, the more pronounced inflammatory response (IL-17 A and RANKL), greater cytokine presence, and faster orthodontic tooth movement (OTM) would appear to be determined by lower estrogen levels, manifesting, thus, a correlation between sex and hormone levels [69; 70]. OT with lingual braces induces a distinct inflammatory response, as evidenced by altered levels of cytokines and cellular composition in saliva. In fact, higher levels of chemokine ligand 2, IL-17A and IL-6 (two to four times higher) were found in patients with lingual braces than in those with fixed labial braces, as well as lower levels, detected by enzyme-linked immunosorbent assay (ELISA) tests, of defensins in the saliva of patients with lingual OT [71; 72; 73]. In the comparison of inflammatory reactivity between aligners and lingual devices, analyzing GCF biomarkers revealed that higher levels of TNF-a were also shown in situations where aligners were used compared to lingual fixed appliances. However, significant levels of interleukins (IL-1 alpha, IL-1 beta, IL-2, IL-6, and IL-8) and TNF-alpha were recorded in GCF in both treatments [74]. Salivary chemokine secretion between the lingual and labial braces groups showed higher secretion of C motif chemokine ligand 2(CCL2), CCL1, CCL2, CCL5 and C-X-C motif chemokine ligand 8 (CXCL8) in subjects with labial braces.