Inflammation and inflammatory control in interstitial cystitis/bladder pain syndrome: Associations with painful symptoms

Abstract

Toll-like receptors (TLR) are known to play a role in chronic pain, from animal models and limited research in humans, but their role in interstitial cystitis/bladder pain syndrome (IC/BPS) is unknown. Similarly, alterations of the hypothalamic-pituitary-adrenal axis have been reported in some pain conditions. Our objectives were to identify inflammatory processes that might distinguish individuals with IC/BPS from healthy controls (HC) and to examine their associations with IC/BPS symptoms. Female participants (58IC/BPS patients and 28HCs) completed pain and urinary symptom questionnaires and collected saliva for cortisol as part of the Multidisciplinary Approach to Pelvic Pain study. Inflammatory cytokines were assayed in plasma, and in TLR-2- and TLR-4-stimulated peripheral blood mononuclear cells. Controlling for BMI and negative affect, between-group differences were analyzed by general linear models, and relationships between symptoms and inflammatory variables were analyzed by regression. Compared to HCs, IC/BPS patients had higher levels of plasma interleukin-6 (P=.040), greater interleukin-1β responsive to TLR-2 stimulation (P=.040), and flatter diurnal cortisol slopes (P=.010), indicating inflammatory dysregulation. In IC/BPS patients, inflammation after TLR-4 stimulation was associated with multiple symptoms, including genitourinary pain (P=.010), sexual pain (P=.002), and marginally with urinary symptoms (P=.068). Genitourinary pain severity (P=.008), frequency (P=.001), and pain with intercourse (P=.002) were strongly associated with TLR-4 inflammatory response. TLR-4 appears to play a central role in painful symptoms of IC/BPS patients, which may be linked to poor endogenous inflammatory control. These findings may help to identify new mechanisms in IC/BPS and lead to new therapeutic approaches.

Keywords: Bladder pain syndrome; Hypothalamic–pituitary–adrenal axis; Inflammation; Interstitial cystitis; Pelvic pain; Toll-like receptors.