Abstract
Recent studies suggest that janus-activated kinases–signal transducer and activator of transcription signaling pathways contribute to increased voiding frequency and referred pain of cyclophosphamide (CYP)-induced cystitis in rats. Potential upstream chemical mediator(s) that may be activated by CYP-induced cystitis to stimulate JAK/STAT signaling are not known in detail. In these studies, members of the interleukin (IL)-6 family of cytokines including, leukemia inhibitory factor (LIF), IL-6, and ciliary neurotrophic factor (CNTF) and associated receptors, IL-6 receptor (R) α, LIFR, and gp130 were examined in the urinary bladder in control and CYP-treated rats. Cytokine and receptor transcript and protein expression and distribution were determined in urinary bladder after CYP-induced cystitis using quantitative, real-time polymerase chain reaction (Q-PCR), western blotting, and immunohistochemistry. Acute (4 h; 150 mg/kg; i.p.), intermediate (48 h; 150 mg/kg; i.p.), or chronic (75 mg/kg; i.p., once every 3 days for 10 days) cystitis was induced in adult, female Wistar rats with CYP treatment. Q-PCR analyses revealed significant (p ≤ 0.01) CYP duration- and tissue- (e.g., urothelium, detrusor) dependent increases in LIF, IL-6, IL-6Rα, LIFR, and gp130 mRNA expression. Western blotting demonstrated significant (p ≤ 0.01) increases in IL-6, LIF, and gp130 protein expression in whole urinary bladder with CYP treatment. CYP-induced cystitis significantly (p ≤ 0.01) increased LIF-immunoreactivity (IR) in urothelium, detrusor, and suburothelial plexus whereas increased gp130-IR was only observed in urothelium and detrusor. These studies suggest that IL-6 and LIF may be potential upstream chemical mediators that activate JAK/STAT signaling in urinary bladder pathways.
Highlights
Cytokine receptors signal predominantly through janus-activated kinases (JAK)–signal transducer and activator of transcription (STAT) pathways (Dziennis and Alkayed, 2008) and we recently demonstrated that cyclophosphamide (CYP)-induced cystitis of varying duration was associated with enhanced JAK–STAT signaling (Cheppudira et al, 2009)
IL-6, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF) transcript expression in urothelium and detrusor smooth muscle with CYP-induced cystitis The regulation of IL-6, LIF, and CNTF transcripts was examined by Q-PCR analyses (Figures 1A–C) in urothelium and detrusor smooth muscle
LIF mRNA expression in detrusor muscle was significantly increased with each duration of CYP treatment (Figure 1B) and the magnitude of change was consistent across time points
Summary
Cytokine receptors signal predominantly through janus-activated kinases (JAK)–signal transducer and activator of transcription (STAT) pathways (Dziennis and Alkayed, 2008) and we recently demonstrated that cyclophosphamide (CYP)-induced cystitis of varying duration was associated with enhanced JAK–STAT signaling (Cheppudira et al, 2009). Blockade of JAK2 with AG490, a member of the tyrphostin family of tyrosine kinase inhibitors, significantly reduced bladder hyperreflexia and hind paw sensitivity in CYP-treated rats (Cheppudira et al, 2009). In aggregate, these studies demonstrated potential roles for JAK–STAT signaling pathways in contributing to bladder hyperreflexia and referred pain of CYP-induced bladder inflammation (Cheppudira et al, 2009). Bladder pain syndrome (BPS)/interstitial cystitis (IC) is viewed as a one type of chronic pain syndrome characterized by pain, pressure, or discomfort perceived to be bladder related with at least one urinary symptom such as urinary frequency (Hanno et al, 2010)
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