Autocrine effects of interleukin-6 mediate acute-phase proinflammatory and tissue-reparative transcriptional responses of canine bladder mucosa.

Abstract

During early urinary tract infection (UTI) the interplay between invading bacteria and the urothelium elicits a mucosal response aimed at clearing infection. Unfortunately, the resultant inflammation and associated local tissue injury are responsible for patient symptoms. Interleukin-6 (IL-6), a cytokine released during acute UTI, has both pro- and anti-inflammatory effects on other body systems. Within the urothelium, the IL-6 native-tissue origin, the target cell type(s), and ultimate effect of the cytokine on target cells are largely unknown. In the present study we modeled the UTI IL-6 response ex vivo using canine bladder mucosa mounted in Ussing chambers to determine the inflammatory and reparative role of IL-6. We demonstrated that uropathogenic Escherichia coli infection stimulates the synthesis of IL-6 by all urothelial cell layers, with the urothelial cells alone representing the only site of unequivocal IL-6 receptor expression. Autocrine effects of IL-6 were supported by the activation of urothelial STAT3 signaling and SOCS3 expression. Using exogenous IL-6, a microarray approach, and quantitative reverse transcriptase PCR (q-RT-PCR), 5 target genes (tumor necrosis factor alpha, interleukin-1β, matrix metallopeptidase 2, heparan sulfate d-glucosaminyl 3-O-sulfotransferase 3A1, and hyaluronan synthase 2) that have direct or indirect roles in promoting a proinflammatory state were identified. Two of these genes, heparan sulfate d-glucosaminyl 3-O-sulfotransferase 3A1 and hyaluronan synthase 2, are also potentially important mediators of wound repair via the production of glycosaminoglycan components. These findings suggest that IL-6 secretion during acute UTI may serve a dual biological role by initiating the inflammatory response while also repairing urothelial defenses.

• Authors: Michael W Wood, Edward B Breitschwerdt, Jody L Gookin
• Journal: Infection and immunity (Infect Immun) Vol. 79 Issue 2 Pg. 708-15 (Feb 2011) ISSN: 1098-5522 [Electronic] United States
• PMID: 21115724 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Interleukin-6

Topics

• Acute-Phase Reaction (metabolism)
• Animals
• Dogs
• Humans
• Interleukin-6 (metabolism)
• Mucous Membrane (metabolism, microbiology)
• Signal Transduction
• Tissue Culture Techniques
• Urinary Bladder (metabolism, microbiology)
• Uropathogenic Escherichia coli
• Urothelium (metabolism)