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Toll-Like Receptor 4 and Inflammation in Interstitial Cystitis/Painful Bladder Syndrome: Associations with Painful Symptoms

Schrepf AD, Lutgendorf S, O'Donnell M, Luo Y, Bradley CS, Kreder K. Toll-Like Receptor 4 and Inflammation in Interstitial Cystitis/Painful Bladder Syndrome: Associations with Painful Symptoms. Paper presented at: American Psychosomatic Society Annual Scientific Meeting; 2014 Mar 13; San Francisco, CA.


Purpose: Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS) is a condition of unknown etiology characterized by urinary urgency, frequency and pain. We have previously reported cortisol abnormalities associated with symptom severity but IC/PBS symptoms have not previously been examined in the context of inflammatory processes. Methods: Female IC/PBS patients (n = 58) and healthy controls (HC) (n = 28) completed questionnaires, including the female Genitourinary Pain Index (GUPI), Female Sexual Functioning Inventory (FSFI), Interstitial Cystitis Symptom Index (ICSI), and Brief Pain Inventory (BPI) as part of the Multidisciplinary Approach to Pelvic Pain (MAPP) Network baseline assessment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated with Toll-Like Receptor (TLR) 2 and 4 agonists, then assayed for interleukin-6 (IL-6) and Interleukin-1 (IL-1 ) production. Plasma was assayed for IL-6 and C-reactive protein. Subjects collected saliva 3 times a day for 3 days for cortisol assessments. Z-scores were generated for the IL-6 and IL-1 response to TLR2 and TLR4 stimulation in PBMCs. All analyses controlled for body mass index (BMI). Results: Compared to HCs, IC/PBS patients had elevated plasma IL-6 (p = .040), a more robust IL-1 response to TLR2 stimulation (p = .039), and flatter cortisol slope (p = .010) but no differences in CRP. Within the IC/PBS group, higher TLR4 z-scores were associated with worse scores on the GUPI (p = .003), FSFI (p < .001), and ICSI (p = .037) and worse non-pelvic pain as indicated on the BPI body map (p = .04). The TLR4 z-score was also associated with pain frequency and intensity (p's < .001) and pain during intercourse (p < .001) and but did not predict either urinary urgency or frequency. Conclusions: These findings indicate that IC/PBS is marked by inflammatory dysregulation, including an elevated response to TLR2 stimulation and a flatter diurnal cortisol pattern. The TLR4 cytokine response was strongly associated with a variety of pain responses, a pattern hypothesized to be consistent with spinal glia pain amplification as a potential mechanism underlying IC/PBS pain.

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