The role(s) of cytokines/chemokines in urinary bladder inflammation and dysfunction

Abstract

Bladder pain syndrome (BPS)/interstitial cystitis (IC) is a chronic pain syndrome characterized by pain, pressure, or discomfort perceived to be bladder related and with at least one urinary symptom. It was recently concluded that 3.3-7.9 million women (>18 years old) in the United States exhibit BPS/IC symptoms. The impact of BPS/IC on quality of life is enormous and the economic burden is significant. Although the etiology and pathogenesis of BPS/IC are unknown, numerous theories including infection, inflammation, autoimmune disorder, toxic urinary agents, urothelial dysfunction, and neurogenic causes have been proposed. Altered visceral sensations from the urinary bladder (i.e., pain at low or moderate bladder filling) that accompany BPS/IC may be mediated by many factors including changes in the properties of peripheral bladder afferent pathways such that bladder afferent neurons respond in an exaggerated manner to normally innocuous stimuli (allodynia). The goals for this review are to describe chemokine/receptor (CXCL12/CXCR4; CCL2/CCR2) signaling and cytokine/receptor (transforming growth factor (TGF-β)/TGF-β type 1 receptor) signaling that may be valuable LUT targets for pharmacologic therapy to improve urinary bladder function and reduce somatic sensitivity associated with urinary bladder inflammation.

Figure 1

Potential etiologic cascade and pathogenesis underlying painful bladder syndrome (BPS)/interstitial cystitis (IC). It is likely that BPS/IC has a multifactorial etiology that may act predominantly through one or more pathways resulting in the typical symptom-complex. There is a lack of consensus regarding the etiology or pathogenesis of BPS/IC but a number of proposals include a “leaky epithelium,” release of neuroactive compounds at the level of the urinary bladder with mast cell activation, “awakening” of C-fiber bladder afferents, and upregulation of inflammatory mediators including cytokines and chemotactic cytokines (chemokines). Inflammatory mediators can affect CNS and PNS neural circuitry including central “wind-up” and nociceptor sensitization resulting in chronic bladder pain and voiding dysfunction. BPS/IC is associated with diseases affecting other viscera and pelvic floors. See text for additional details. Figure adapted from [32].