Autocrine effects of interleukin-6 mediate acute-phase proinflammatory and tissue-reparative transcriptional responses of canine bladder mucosa.
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.
Center for Comparative Medicine and Translational Research and Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606, USA.
Michael W
MW
Wood
Edward B
EB
Breitschwerdt
Jody L
JL
Gookin
D000210:Acute-Phase Reaction / Q000378:metabolism*; D000818:Animals; D004285:Dogs; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D009092:Mucous Membrane / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D001743:Urinary Bladder / Q000378:metabolism* / Q000382:microbiology; D056689:Uropathogenic Escherichia coli; D019459:Urothelium / Q000378:metabolism
D015850:Interleukin-6