Renal cytokine responses in acute Escherichia coli pyelonephritis in IL-6-deficient mice

The aim of this study was to investigate the influence of IL-6 on mortality, bacterial growth and cytokine expression in experimental acute pyelonephritis. Female IL-6-deficient mice and their wild-type counterparts, 8-10 weeks old, were infected with Escherichia coli CFT 073 or injected with NaCl 0.9% (w/v) via the urethra and thereafter obstructed for 6 h. Animals were killed at 48 h, 6 days or 8 weeks and cytokine and bacterial renal levels were assessed at each time point. We found that IL-6-deficient mice had increased mortality and extensive renal bacterial growth on day 6, compared with wild-type mice (P < 0.05) and the histopathological changes were generally more severe and widespread in the IL-6-deficient mice. Peak mRNA expression of IL-1beta, IL-4, IL-10, IL-12 and interferon-gamma (IFN-gamma) occurred 48 h after infection in both IL-6 knock out and wild-type mice. Transforming growth factor-beta (TGF-beta) levels also peaked at 48 h in E. coli-infected wild-type mice, while in the IL-6-deficient strain both TGF-beta mRNA and protein levels were significantly lower at 48 h than wild-type levels (P < 0.0008 and P < 0.03, respectively) and remained stationary throughout the study period. Animals injected with NaCl 0.9% (w/v) displayed a similar decrease in TGF-beta expression (P < 0.02). When splenocytes from the IL-6-deficient mice were incubated with murine recombinant IL-6, TGF-beta levels increased to those of wild-type mice. No increase was observed when splenocytes from wild-type mice were incubated with the same doses of rIL-6. We therefore conclude that IL-6 plays an important role in bacterial clearance and directly influences the TGF-beta levels in experimental acute pyelonephritis. We also demonstrate that urethral obstruction per se induces an increase in TGF-beta the magnitude of which is decreased in IL-6-deficient mice.