IL-15, IL-18 and IL-21 Along the Stress–Smoking–Periodontal Health Axis: A Cross-Sectional Study in Mexican Adults

From a psychoneuroimmunology standpoint, stress and cigarette smoking are plausible modulators of periodontal inflammation through neuroendocrine-immune pathways and cytokine networks. Interleukin-18 (IL-1 family), interleukin-21 (common γ-chain cytokine), and interleukin-15 (tissue-resident lymphocyte activation/homeostasis) are mechanistically relevant candidates to characterize in relation to these exposures. We aimed to quantify serum IL-15, IL-18, and IL-21 and examine their associations with stress, smoking, and periodontal status in Mexican adults. <b>Methods</b>: Cross-sectional study (<i>n</i> = 65; 18-60 years; 70.8% female). Smoking status (23.1% smokers) and periodontal status were recorded; due to low periodontitis frequency (<i>n</i> = 3), periodontal status was analyzed as healthy (23.1%) versus periodontal disease (76.9%; gingivitis + periodontitis). Stress was assessed using the 18-item Symptomatic Stress Questionnaire and dichotomized as no/low stress (0-10; 52.3%) versus pathological stress (11-54; 47.7%). Systolic and diastolic blood pressure were recorded. IL-15, IL-18, and IL-21 were measured in serum by immunoassay. Analyses used medians (IQR), Mann-Whitney U tests with rank-biserial effect sizes, and exploratory Benjamini-Hochberg false discovery rate (FDR) adjustment across the nine primary cytokine-by-contrast tests; correlations with age and diastolic blood pressure were exploratory. <b>Results</b>: Cytokine distributions were right-skewed, particularly for IL-21. Across smoking, stress, and periodontal-status contrasts, no comparison met q < 0.05 after FDR adjustment. Effect-size patterns were heterogeneous rather than uniformly monotonic across exposures (e.g., IL-18 showed higher central tendency in healthy vs. periodontal disease; IL-21 showed higher central tendency in no/low stress vs. pathological stress), indicating substantial inter-individual variability in circulating cytokines within this cohort. <b>Conclusions</b>: In this exploratory cross-sectional sample, serum IL-15, IL-18, and IL-21 did not show robust, multiplicity-resistant differences by smoking, stress, or periodontal status. The findings provide a transparent description of distributional properties and hypothesis-generating patterns that motivate larger, longitudinal studies with repeated cytokine sampling, standardized periodontal assessment, and improved control of key confounders to clarify the relevance of these cytokines to periodontal inflammation under behavioral exposures.