IL-38 is a member of the IL-1 superfamily. It is an anti-inflammatory cytokine with protective role.It is involved in the pathogenesis of several diseases including cardiovascular diseases, cerebrovascular disease, pulmonary disease, infectious diseases , autoimmune diseases, Diabetes mellitus etc. It was first identified in 2001 from organs associated with immune response and has a molecular weight of 17kDa.The gene is located in the chromosome 2q13-14.1 clustered with the IL-1 family. The interleukin was previously referred to as IL-1F10 and IL-1HY2 and is secreted by epithelial cells, monocytes, macrophages and immune cells. It lacks a signal peptide hence secreted from the cells by different unknown mechanisms. ILâ€1R1, ILâ€36R, and ILâ€1RAPL1 are the main receptors of ILâ€38. The structure has 37% similarity to IL-1Ra and 41% similarity to IL-36Ra, by binding to IL-1R1 and IL-36R it inhibits NF-KB, ERK, JNK, P38.It exists in 2 forms , the full (aa 1-152) and the truncated form (aa 20-152). Proteases that are currently unknown cleave the pre-cursor form at the N terminal end allowing activation. Despite its largely anti-inflammatory role Pan et al, Mora et al, and Van de Veerdonk et al have reported that IL-38, upregulated IL-6 and IL-22 levels depending on the concentration, form (full length or truncated form), and the presence of external stimuli. However, information available on this particular biomolecule is minimal, preliminary, not definitive, necessitating further research to fully understand its characteristics.
In pulmonary diseases, IL-38 has anti-inflammatory and anti-fibrotic effect. Likewise, it reduces neuroinflammation in neurodegenerative illnesses like Alzheimer's. In 2023, Wei et al. showed that IL-38 suppressed macrophage- mediated inflammation and decreased myocardial apoptosis by blocking the activation of the NLRP3 inflammasome. In an attempt to combat obesity and insulin resistance, it also suppresses preadipocyte differentiation by upregulating GATA-3 expression, lowers triglyceride synthesis, and reduces adipocyte size. Furthermore, it lowers the levels of Total Cholesterol, Triglycerides, and Low- density lipoproteins as well as the production of IL-1β, IL-6, and Monocyte chemotactic protein-1, which enhances lipid and glucose metabolism and lowers the risk of cardiovascular diseases. According to de Graaf et al., overweight people with a high risk of CVDs had considerably lower serum IL-38 levels than healthy people. The above literature indicates the protective role of IL-38 in cardiovascular system.
Huard et al,2023, Lauritano et al, 2023, reported that IL-38 plays an important role in the pathogenesis of autoimmune diseases by inactivating immune cells and inflammatory responses. It further, inhibits the release of inflammatory cytokines and chemotaxis. Additionally, it promotes the activity of regulatory T cells to suppress autoimmune responses. IL-38 also regulates the release of cytokines secreted by Th1 and Th17 cells. Further, Yan Li et al in their study demonstrated that IL-38 reduced the levels of GATA3, GLUT4, inflammatory cytokines like IL-1b, IL-6, MCP-1, reduced the number of lipid droplets indicating its protective role in inhibiting adipogenesis. Therefore, it can be inferred that IL-38 has a predominantly anti-inflammatory role in the pathogenesis of multiple diseases. The role of IL-38 in the pathogenesis of type 2 diabetes mellitus has been investigated and discussed by few authors. Felicia Gurau et al, 2021 observed considerably higher plasma concentrations of IL-38 in T2DM with and without diabetic nephropathy patients. Likewise , shahad Nassurat et al in 2024, reported upregulated serum levels of IL-38 in T2DM with and without diabetic neuropathy. Similar trend in the IL-38 levels have been reported in gestational diabetes mellitus and in children with T2DM. On the contrary, Tingqi Zhao et al, 2022, observed reduced serum levels of IL-38 and negative correlation with IL-17 in T2DM.The author suggested that IL-38 could be a marker for diagnosis of T2DM. Furthermore, it has been suggested that IL-38 increases insulin sensitivity in T2DM. However, the precise role and the pathways associated with this biomolecule is unclear and needs to be explored in future studies.
Diabetes and Periodontitis share similar pathophysiology and diabetes is a risk factor for periodontitis. The role of IL-38 in periodontitis has been investigated only in two studies by Korkmaz et al, 2023 and Toraman & colleagues in 2024. The former in their study demonstrated higher levels of salivary and serum IL-38 in the periodontitis group when compared with healthy and gingivitis group. Salivary levels of IL-38 were higher in stage III, grade B and stage III, grade C subjects when compared to periodontal health and gingivitis. Similarly, serum IL- 38 levels were higher in periodontitis group when compared to periodontal health and gingivitis. Based on their results the authors concluded that IL-38 could be used as a marker to identify periodontal disease activity. On the contrary, Toraman & colleagues demonstrated reduced salivary levels of IL-38 in periodontitis group when compared to periodontal health and gingivitis. The role of IL-38 in periodontitis needs further clarity and the role of IL-38 in T2DM associated periodontitis has never been studied till date and needs to be investigated. Further the effect of non-surgical periodontal therapy (NSPT) on the levels of IL-38 has never been studied. Hence, this study was carried out. We hypothesis that the salivary and serum levels of IL-38 will be dysregulated in T2DM associated periodontitis when compared with periodontal health. Further treatment intervention by NSPT will alter IL-38 levels favorably towards periodontal health.
The present study aims to evaluate the role of IL-38 in the pathogenesis of Type 2 Diabetes mellitus (T2DM) associated periodontitis, as well as to detect the influence of NSPT on the serum and saliva levels of IL-38 to evaluate its utility as a biomarker for T2DM associated periodontitis. |