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.

Chronic Prostatitis Affects Male Reproductive Health and Is Associated with Systemic and Local Epigenetic Inactivation of C-X-C Motif Chemokine 12 Receptor C-X-C Chemokine Receptor Type 4

“…In order to analyze, whether the detected impairment of standard semen parameters is in fact associated with CP/CPPS and not with elder age of the patient cohort, we performed age-matched comparative analyses. We considered only young CP/CPPS type IIIb patients (n = 32, median age 27 (range [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32]) and compared those to healthy controls. We still detected a significant association between CP/CPPS and reduced sperm motility (total and progressive, p < 0.001), increased aberrations in sperm morphology (head and tail defects, p < 0.001) and reduced seminal pH (p < 0.001).…”

“…Impairments in the CXCL12/CXCR4 signaling axis, partially caused by epigenetic aberrations of the corresponding gene promoters, have been demonstrated to play a critical role in the progression of a number of malignancies, including prostate, bladder, breast, hepatocellular, pancreatic, lung, basal cell carcinomas and astrocytomas [14,15] . Recently, a significant role of CXCL12 and CXCR4 was also reviewed for bladder pain syndrome/interstitial cystitis, a chronic pain syndrome of the bladder comparable to CP/CPPS in its proposed etiology [16] .…”

Predictive role of serum and urinary cytokines in invasion and recurrence of bladder cancer

“…Of these, high concentrations of six cytokines (IP-10, IL-1RA, IL-4, IL-10, PDGF and VEGF) have been found associated with poorer RFS. However, all the cytokines and growth factors are also released in urine of cystitis patients, [11][12][13] and hence, it is necessary to know the concentrations in urine of cancer patients compared to patients with cystitis if these markers have to be used as biomarkers of recurrence in future. To address this issue, a small cohort of patients with cystitis was recruited, and it was found that the concentrations of VEGF and IP-10 were significantly higher in cancer cases compared to both controls and patients with cystitis.…”

Effects of CYP-Induced Cystitis on Growth Factors and Associated Receptor Expression in Micturition Pathways in Mice with Chronic Overexpression of NGF in Urothelium

“…Many chemical mediators (e.g., neurotrophins, cytokines, chemokines, neuropeptides) produced in micturition reflex pathways following CYP-induced cystitis may contribute to neurochemical, organizational, functional plasticity in micturition pathways (Arms et al, 2013; Arms et al, 2010; Arms and Vizzard, 2011; Gonzalez et al, 2014a; Gonzalez et al, 2013; Gonzalez et al, 2014b; Schnegelsberg et al, 2010) and referred somatic sensitivity (Guerios et al, 2006; Guerios et al, 2008; Schnegelsberg et al, 2010). These results suggest that chemical mediators upregulated with CYP-induced bladder inflammation in addition to NGF (e.g., neurotrophins, cytokines, chemokines, neuropeptides) contribute to altered growth factor/receptor transcript expression in micturition pathways in NGF-OE mice (Arms et al, 2013; Arms et al, 2010; Arms and Vizzard, 2011; Gonzalez et al, 2014a; Gonzalez et al, 2013; Gonzalez et al, 2014b; Guerios et al, 2006; Guerios et al, 2008; Schnegelsberg et al, 2010).…”