Cytokine profiles in HPV-associated cervical intraepithelial neoplasia.

Abstract

e22517 Background: Persistent high-risk human papillomavirus (HPV) infection is a well-established driver of cervical intraepithelial neoplasia (CIN), yet progression risk varies among patients. Cytokines shape antiviral immunity and tissue remodeling, and cytokine profiling is emerging as a cost-effective tool to stratify CIN risk and refine prognostic assessment in this population. Objective: Our study evaluated serum and cervical mucus cytokine profiles in HPV-negative normal cytology and in low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL), stratified by HPV genotype and viral load. Methods: Ninety women aged 18–80 years were enrolled, including 30 healthy controls and 60 HPV-positive patients with histologically confirmed CIN (LSIL, n = 30; HSIL, n = 30). Levels of 27 cytokines (pg/mL), including FGF, GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, TNF-α, VEGF, and selected chemokines, were measured in serum and cervical mucus using the Bio-Plex Pro Human Cytokine 27-plex assay (Bio-Rad, USA) on a Luminex 200 platform. The IL-10/IL-17A ratio was calculated. Cytokine profiles were stratified by HPV genotype [HPV(−), HPV(+) 16/18, HPV(+) 31–73] and viral load [HPV(−), low ( < 5), high (≥5)]. Data were reported as median (Q1–Q3). Statistical analyses included one-way ANOVA with pairwise t-tests and Bonferroni correction; p < 0.05 was considered significant. Results: Serum: LSIL was characterized by increased GM-CSF, IL-4, IL-7, and IL-8 with decreased IL-2, IL-5, IL-17A, and angiogenic factors (FGF/VEGF); the IL-10/IL-17A ratio was reduced (p < 0.05). HSIL showed increased IL-7, IL-10, TNF-α, IL-8, MCP-1, and FGF with decreased IL-2, IL-5, and IL-17A; the IL-10/IL-17A ratio was increased (p < 0.05). Cervical mucus: LSIL demonstrated increased IL-10, IL-1β/IL-1ra, IL-2, IL-4, TNF-α, and FGF with reduced IL-8 and IP-10. HSIL showed broader immune activation with increased IL-10, IL-12p70, IL-17A, IL-1β, IL-6, TNF-α, GM-CSF, FGF, and VEGF, alongside decreased IL-9, IL-8, and IP-10 (p < 0.05). Conclusions: CIN grade was associated with distinct systemic and local cytokine signatures, with HSIL showing broader proinflammatory activation in cervical mucus and a grade-dependent shift in the serum IL-10/IL-17A ratio, consistent with compartmentalized immune dysregulation in HPV-associated disease.