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Macrophage Migration Inhibitory Factor Mediates PAR-Induced Bladder Pain
Dimitrios E Kouzoukas1, Katherine L Meyer-Siegler2, Fei Ma3
1Research and Development, Lexington Veterans Affairs Medical Center, Lexington, Kentucky, United States of America; Saha Cardiovascular Research Center, University of Kentucky, Lexington, Kentucky, United States of America.
Plos One
|May 29, 2015
Summary
Activation of bladder protease-activated receptors (PAR) triggers the release of macrophage migration inhibitory factor (MIF), leading to hypersensitivity and potential therapeutic targets for bladder pain.
Area of Science:
- Urology
- Immunology
- Pain Research
Background:
- Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine found in urothelial cells.
- Protease-activated receptors (PARs) are present in urothelial cells and implicated in bladder inflammation.
- Thrombin, a PAR1 and PAR4 activator, is known to induce urothelial MIF release.
Purpose of the Study:
- To investigate the hypothesis that urothelial PAR1 or PAR4 receptor stimulation releases MIF, activating MIF receptors and mediating bladder inflammation and pain.
- To examine the effects of specific bladder PAR receptor activation on MIF release, bladder pain, micturition, and histological changes.
Main Methods:
- In vitro assessment of MIF release from human urothelial cells (UROtsa) exposed to PAR1 or PAR4 activating peptides (AP).
- In vivo studies in mice involving intravesical administration of PAR1- or PAR4-AP to evaluate MIF release, abdominal hypersensitivity, micturition parameters, and bladder histology.
- Analysis of bladder MIF and MIF receptor (CXCR4) expression via real-time RT-PCR and quantitative immunofluorescence.
- Investigation of the effects of MIF and CXCR4 antagonism.
Main Results:
- PAR1- and PAR4-AP stimulated MIF release in both in vitro and in vivo models.
- Intravesical PAR1- or PAR4-AP induced abdominal hypersensitivity 24 hours post-treatment, without altering micturition or bladder histology.
- PAR4-AP demonstrated greater efficacy, increasing bladder MIF and urothelial CXCR4 expression.
- MIF antagonism (ISO-1) abolished PAR4-induced hypersensitivity and reduced PAR1-induced hypersensitivity, while CXCR4 antagonism (AMD3100) only partially inhibited PAR4-induced hypersensitivity.
Conclusions:
- Bladder PAR activation leads to urothelial MIF release and signaling, partly via CXCR4, causing abdominal hypersensitivity without apparent bladder inflammation.
- This PAR-induced bladder pain model may be relevant for understanding Interstitial Cystitis/Painful Bladder Syndrome (IC/PBS).
- MIF presents a potential novel therapeutic target for managing bladder pain in IC/PBS patients.
