Abstract

Objective Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common urological condition in men. Although disruption of the Th17 (T helper 17)/Treg (regulatory T) balance has been implicated in its pathogenesis, the upstream drivers of this immune imbalance remain incompletely understood. This study investigated whether interleukin-6 (IL-6) is associated with altered Th17/Treg homeostasis and impaired Treg function in experimental autoimmune prostatitis (EAP). Methods An EAP model was generated in NOD mice through immunization with prostate antigen. Th17/Treg cell profiles were determined by flow cytometry, cytokine concentrations by enzyme-linked immunosorbent assay (ELISA), and signal transducer and activator of transcription 5a (STAT5a) expression by western blotting and immunohistochemistry (IHC). In vivo IL-6 inhibition was used to assess its effects on Th17/Treg balance and Treg suppressive function, whereas in vitro experiments examined the effects of IL-6 on Treg function and naïve CD4 + T-cell differentiation. Results Relative to control mice, EAP mice showed higher serum IL-6 concentrations (5.28 ± 0.54 vs. 3.36 ± 0.46 pg/mL, p < 0.01), together with disturbed Th17/Treg homeostasis, as reflected by expansion of Th17 cells (1.72% ± 0.18% vs. 0.98% ± 0.08%, p < 0.001) and reduction of Treg cells (3.99% ± 0.97% vs. 5.46 % ± 0.53%, p < 0.05). Suppressive activity of Treg cells was also diminished (6.56% ± 0.80% vs. 12.41% ± 3.49%, p < 0.05). In vitro, IL-6 shifted naïve CD4 + T-cell differentiation toward the Th17 phenotype while limiting Treg generation and impairing Treg suppressive activity. Mechanistically, IL-6 stimulation reduced STAT5a and p-STAT5a expression in Treg cells. Pharmacological inhibition of IL-6 partially restored Treg function and alleviated inflammatory pathology in EAP mice. Conclusion IL-6 is linked to Th17/Treg imbalance and Treg dysfunction in EAP, possibly through inhibition of STAT5a signaling, and IL-6-related pathway