Faculty Collaboration Database

Antagonism of macrophage migration inhibitory factor decreases cyclophosphamide cystitis in mice. Neurourol Urodyn 2010 Nov;29(8):1451-7

Date

02/04/2010

Pubmed ID

20127836

DOI

10.1002/nau.20878

Scopus ID

2-s2.0-78349283969 (requires institutional sign-in at Scopus site)   20 Citations

Abstract

AIMS: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine found pre-formed in the urothelium. During inflammation, MIF is released into the bladder lumen and bladder MIF mRNA is upregulated. Since MIF also has tautomerase activity and blocking tautomerase activity also blocks MIF's biological activity, we hypothesized that blocking MIF's tautomerase activity would prevent bladder inflammation. Therefore, we examined the effects of a MIF tautomerase inhibitor (ISO-1; also blocks biological activity) on cyclophosphamide (CYP)-induced cystitis in mice.

METHODS: Mice receiving CYP (300 mg/kg; i.p.) to induce cystitis or saline (control) were treated either with ISO-1 (20 mg/kg; i.p.; daily) or vehicle (20% DMSO; i.p.; daily) for 2 days. After 2 days, micturition volume and frequency in awake mice were recorded and also mechanical sensitivity to abdominal stimulation using von Frey monofilaments. Bladders were collected under anesthesia and examined histologically, nerve growth factor levels were assayed in bladder homogenates, and production of inflammatory cytokines in the bladder was determined using a targeted array.

RESULTS: CYP treatment resulted in decreased micturition volume, increased frequency, decreased threshold, increased histological signs of cystitis, increased bladder NGF levels and production of inflammatory cytokines when compared to the control group. Treatment with ISO-1 prevented or greatly decreased all these changes.

CONCLUSION: Antagonizing MIF's activity with a systemic MIF tautomerase inhibitor was able to prevent or greatly reduced chemical cystitis in mice, thus indicating the MIF mediates bladder inflammation in this model. MIF represents a novel and important modulator of cystitis.

Author List

Vera PL, Iczkowski KA, Howard DJ, Jiang L, Meyer-Siegler KL

MESH terms used to index this publication - Major topics in bold

Animals
Cyclophosphamide
Cystitis
Cytokines
Disease Models, Animal
Enzyme Inhibitors
Female
Hyperalgesia
Inflammation Mediators
Intramolecular Oxidoreductases
Isoxazoles
Macrophage Migration-Inhibitory Factors
Male
Mechanotransduction, Cellular
Mice
Mice, Inbred C57BL
Nerve Growth Factor
Sensory Thresholds
Urinary Bladder
Urination