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Cyclophosphamide-induced cystitis increases bladder CXCR4 expression and CXCR4-macrophage migration inhibitory factor association. PLoS One 2008;3(12):e3898

Date

12/11/2008

Pubmed ID

19066630

Pubmed Central ID

PMC2588654

DOI

10.1371/journal.pone.0003898

Scopus ID

2-s2.0-57549116143   29 Citations

Abstract

BACKGROUND: Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine involved in cystitis and a non-cognate ligand of the chemokine receptor CXCR4 in vitro. We studied whether CXCR4-MIF associations occur in rat bladder and the effect of experimental cystitis.

METHODS AND FINDINGS: Twenty male rats received saline or cyclophosphamide (40 mg/kg; i.p.; every 3(rd) day) to induce persistent cystitis. After eight days, urine was collected and bladders excised under anesthesia. Bladder CXCR4 and CXCR4-MIF co-localization were examined with immunhistochemistry. ELISA determined MIF and stromal derived factor-1 (SDF-1; cognate ligand for CXCR4) levels. Bladder CXCR4 expression (real-time RTC-PCR) and protein levels (Western blotting) were examined. Co-immunoprecipitations studied MIF-CXCR4 associations.Urothelial basal and intermediate (but not superficial) cells in saline-treated rats contained CXCR4, co-localized with MIF. Cyclophosphamide treatment caused: 1) significant redistribution of CXCR4 immunostaining to all urothelial layers (especially apical surface of superficial cells) and increased bladder CXCR4 expression; 2) increased urine MIF with decreased bladder MIF; 3) increased bladder SDF-1; 4) increased CXCR4-MIF associations.

CONCLUSIONS: These data demonstrate CXCR4-MIF associations occur in vivo in rat bladder and increase in experimental cystitis. Thus, CXCR4 represents an alternative pathway for MIF-mediated signal transduction during bladder inflammation. In the bladder, MIF may compete with SDF-1 (cognate ligand) to activate signal transduction mediated by CXCR4.

Author List

Vera PL, Iczkowski KA, Wang X, Meyer-Siegler KL

Author

Kenneth A. Iczkowski MD Professor in the Pathology department at Medical College of Wisconsin




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

Animals
Body Weight
Chemokine CXCL12
Cyclophosphamide
Cystitis
Macrophage Migration-Inhibitory Factors
Male
Protein Binding
Rats
Rats, Sprague-Dawley
Receptors, CXCR4
Reverse Transcriptase Polymerase Chain Reaction
Sodium Chloride
Up-Regulation
Urinary Bladder
Urothelium
jenkins-FCD Prod-400 0f9a74600e4e79798f8fa6f545ea115f3dd948b2